WO2017037567A1 - Régulateurs de la frataxine - Google Patents

Régulateurs de la frataxine Download PDF

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Publication number
WO2017037567A1
WO2017037567A1 PCT/IB2016/055013 IB2016055013W WO2017037567A1 WO 2017037567 A1 WO2017037567 A1 WO 2017037567A1 IB 2016055013 W IB2016055013 W IB 2016055013W WO 2017037567 A1 WO2017037567 A1 WO 2017037567A1
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Prior art keywords
frataxin
bet
optionally substituted
pharmaceutically acceptable
subject
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PCT/IB2016/055013
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English (en)
Inventor
Eugene Lvovich Piatnitski Chekler
Leslie Anthony DAKIN
Lyn Howard Jones
Joseph Fouad NABHAN
Mathew Tyler PLETCHER
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Pfizer Inc.
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Publication of WO2017037567A1 publication Critical patent/WO2017037567A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to regulators of frataxin and, in particular, to methods of regulating the level of frataxin or the expression of frataxin in a cell or subject, comprising administering to the cell or subject a BET-family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof. Associated methods of treatment, pharmaceutical uses and pharmaceutical compositions are also described.
  • BACKGROUND Friedreich's ataxia also called FA or FRDA
  • FA BACKGROUND Friedreich's ataxia
  • the first symptoms of the condition are usually gait ataxia or difficultly walking, but overtime the symptoms worsen and spread resulting in degeneration of the spinal cord, peripheral nerves and cerebellum.
  • the disorder also causes problems in the spine and loss of tendon reflex.
  • Most people with Friedreich's ataxia develop scoliosis (a curving of the spine to one side), which often requires surgical intervention for treatment.
  • Dysarthria slowness and slurring of speech
  • Other symptoms that may occur include chest pain, shortness of breath, and heart palpitations.
  • Friedreich's ataxia is caused by reduced expression of frataxin (FXN) as a result of inheriting two copies of the mutated FXN gene which disrupts the normal production of frataxin.
  • Frataxin is found in the mitochondria and research suggests that without a normal level of frataxin, certain cells in the body (especially peripheral nerve, spinal cord, brain and heart muscle cells) cannot effectively produce energy and it is further hypothesized that these cells experience oxidative stress due to the buildup of toxic byproducts.
  • Frataxin is initially synthesized in vivo as a precursor polypeptide which is in turn directed to the mitochondrial matrix where it is proteolytically cleaved by mitochondrial processing peptidase to the mature form of frataxin via a processing intermediate frataxin ("The in vitro mitochondrial two-step maturation of human frataxin.” Stephane Schmucker et al, Human Molecular Genetics, 2008, vol 17 no 22, p3521- 3531). It is also thought that reduced expression of frataxin results in the nervous system, heart, and pancreas being particularly susceptible to damage from free radicals.
  • This invention relates to a method of regulating the expression of frataxin in a cell or a subject, comprising administering to the cell or the subject in need thereof a therapeutically effective amount of a BET- family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of increasing the expression of frataxin in a cell or a subject, comprising administering to the cell or the subject in need thereof a therapeutically effective amount of a BET- family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of increasing the expression of frataxin in a cell or a subject which cell or subject has decreased frataxin expression when compared to a healthy control cell or healthy subject, comprising administering to the cell or the subject in need thereof a therapeutically effective amount of a BET- family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of increasing the level of frataxin in a cell or a subject, comprising administering to the cell or the subject in need thereof a therapeutically effective amount of a BET- family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of increasing the level of frataxin in a cell or a subject which cell or subject has decreased level of frataxin when compared to a healthy control cell or healthy subject, comprising administering to the cell or the subject in need thereof a therapeutically effective amount of a BET- family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating a condition, disease or disorder, or the symptoms associated with the condition, disease or disorder, which condition, disease or disorder is associated with decreased frataxin expression, comprising administering to a subject in need thereof a therapeutically effective amount of a BET- family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating a condition, disease or disorder, or the symptoms associated with the condition, disease or disorder, which condition, disease or disorder is associated with a decreased level of frataxin, comprising administering to a subject in need thereof a therapeutically effective amount of a BET- family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating Friedreich's ataxia comprising administering to a subject in need thereof a therapeutically effective amount of a BET- family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a BET-family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition, disease or disorder, or the symptoms associated with the condition, disease or disorder, which condition, disease or disorder is associated with decreased frataxin expression.
  • This invention also relates to a BET-family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition, disease or disorder, or the symptoms associated with the condition, disease or disorder, which condition, disease or disorder is associated with a decreased level of frataxin.
  • This invention also relates to a BET-family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of Friedreich's ataxia.
  • This invention also relates to the use of a BET-family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition, disease or disorder, or the symptoms associated with the condition, disease or disorder, which condition, disease or disorder is associated with decreased frataxin expression.
  • This invention also relates to the use of a BET-family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition, disease or disorder, or the symptoms associated with the condition, disease or disorder, which condition, disease or disorder is associated with a decreased level of frataxin.
  • This invention also relates to the use of a BET-family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of Friedreich's ataxia.
  • This invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a BET- family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of a condition, disease or disorder, or the symptoms associated with the condition, disease or disorder, which condition, disease or disorder is associated with decreased frataxin expression.
  • This invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a BET- family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of a condition, disease or disorder, or the symptoms associated with the condition, disease or disorder, which condition, disease or disorder is associated with a decreased level of frataxin.
  • This invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a BET- family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of Friedreich's ataxia.
  • FIG. 1 shows that BET-family bromodomain inhibitors IBET-762 and JQ-1 (+) increased levels of both intermediate frataxin (bands “i”) and mature frataxin (bands “m”) at 72 hrs by Western blot (two exposures shown) in FRDA GM15850 cells.
  • Figure 2 shows the cytotoxic effects of treatment of the FRDA GM 15850 cells with BET-family bromodomain inhibitors IBET-762 and JQ-1 (+) (protein concentrations (mg/ml) for the resultant lysates).
  • FIG. 3 shows that a minimally cyctotoxic concentration of BET-family bromodomain inhibitor JQ-1 (+) increased levels of both intermediate frataxin (bands “i”) and mature frataxin (bands “m”) at 72 hrs by Western blot (two exposures shown) in FRDA GM 15850 cells. Results from DMSO treated AG14725 healthy cells control are also shown.
  • Figure 4 shows pixel densitometry quantification (base line corrected) of immunopositive bands corresponding to mature frataxin from the Western blot of Figure 3. An approximately 1.5 fold increase was observed at 25nM and 50nM treatment with BET-family bromodomain inhibitor JQ-1 (+) when compared to DMSO vehicle treated controls (p ⁇ 0.05).
  • Figure 5 shows a similar cellular toxicity profile (LD 50 ) for both FRDA GM 15850 lymphoblast cells and healthy AG14725 upon treatment with BET-family bromodomain inhibitor JQ-1 (+), suggesting that a lower level of frataxin does not sensitize cells to toxicitiy by the BET-family bromodomain inhibitor JQ-1 (+).
  • FIG. 6 shows that BET-family bromodomain inhibitors with a variety of chemical scaffolds (compounds 1 - 6), increased levels of both intermediate frataxin (bands “i”) and mature frataxin (bands “m”) at 72 hrs by Western blot (two exposures shown) in FRDA GM 15850 cells.
  • FIG. 7 shows that BRD4 knockdown using the BRD4 siRNA smartpool or treatment with BET-family bromodomain inhibitor JQ-1 (+) increased levels of both intermediate frataxin (bands “i”) and mature frataxin (bands “m”) at 72 hrs by Western blot (two exposures shown) in FRDA GM03665 fibroblasts.
  • FIG. 8 shows that knockdown of other BET-family proteins using siRNA smartpools also resulted in increased levels of both intermediate frataxin (bands “i”) and mature frataxin (bands “m”) at 72 hrs by Western blot (two exposures shown) in FRDA GM03665 fibroblasts.
  • the present invention relates to methods of regulating the level of frataxin or the expression of frataxin in a cell or subject, comprising administering to the cell or subject a BET-family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to novel pharmaceutical methods, and associated methods of treatment, utilising a BET-family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof.
  • This invention relates to a method of regulating the expression of frataxin in a cell or a subject, comprising administering to the cell or the subject in need thereof a therapeutically effective amount of a BET- family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of increasing the expression of frataxin in a cell or a subject, comprising administering to the cell or the subject in need thereof a therapeutically effective amount of a BET- family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of increasing the expression of frataxin in a cell or a subject which cell or subject has decreased frataxin expression when compared to a healthy control cell or healthy subject, comprising administering to the cell or the subject in need thereof a therapeutically effective amount of a BET- family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of increasing the level of frataxin in a cell or a subject, comprising administering to the cell or the subject in need thereof a therapeutically effective amount of a BET- family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of increasing the level of frataxin in a cell or a subject which cell or subject has decreased level of frataxin when compared to a healthy control cell or healthy subject, comprising administering to the cell or the subject in need thereof a therapeutically effective amount of a BET- family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating a condition, disease or disorder, or the symptoms associated with the condition, disease or disorder, which condition, disease or disorder is associated with decreased frataxin expression, comprising administering to a subject in need thereof a therapeutically effective amount of a BET- family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating a condition, disease or disorder, or the symptoms associated with the condition, disease or disorder, which condition, disease or disorder is associated with a decreased level of frataxin, comprising administering to a subject in need thereof a therapeutically effective amount of a BET- family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating Friedreich's ataxia comprising administering to a subject in need thereof a therapeutically effective amount of a BET- family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a BET-family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition, disease or disorder, or the symptoms associated with the condition, disease or disorder, which condition, disease or disorder is associated with decreased frataxin expression.
  • This invention also relates to a BET-family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition, disease or disorder, or the symptoms associated with the condition, disease or disorder, which condition, disease or disorder is associated with a decreased level of frataxin.
  • This invention also relates to a BET-family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of Friedreich's ataxia.
  • This invention also relates to the use of a BET-family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition, disease or disorder, or the symptoms associated with the condition, disease or disorder, which condition, disease or disorder is associated with decreased frataxin expression.
  • This invention also relates to the use of a BET-family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition, disease or disorder, or the symptoms associated with the condition, disease or disorder, which condition, disease or disorder is associated with a decreased level of frataxin.
  • This invention also relates to the use of a BET-family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of Friedreich's ataxia.
  • This invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a BET- family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of a condition, disease or disorder, or the symptoms associated with the condition, disease or disorder, which condition, disease or disorder is associated with decreased frataxin expression.
  • This invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a BET- family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of a condition, disease or disorder, or the symptoms associated with the condition, disease or disorder, which condition, disease or disorder is associated with a decreased level of frataxin.
  • This invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a BET- family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of Friedreich's ataxia.
  • the terms “treat” or “treating” refer to partially or completely alleviating, inhibiting, ameliorating and/or relieving a condition, disease or disorder, or the symptoms associated with the condition, disease or disorder from which a patient or subject has been diagnosed as suffering or from which a patient or subject is suspected to suffer.
  • the terms “treat” or “treating” also refer to slowing of the advancement of a condition, disease or disorder, or the symptoms associated with the condition, disease or disorder from which a patient or subject has been diagnosed as suffering or from which a patient or subject is suspected to suffer.
  • the terms “treat” or “treating” also refer to regression of the condition, disease or disorder, including regression of the symptoms associated with the condition, disease or disorder, from which a patient or subject has been diagnosed as suffering or from which a patient or subject is suspected to suffer.
  • the terms “treat” or “treating” also refer to the prevention of a condition, disease or disorder, or the symptoms associated with the condition, disease or disorder from which a patient or subject has been diagnosed as suffering or from which a patient or subject is suspected to suffer.
  • the terms “treat” or “treating” also refer to the prevention of the advancement of a condition, disease or disorder, or the symptoms associated with the condition, disease or disorder, from which a patient or subject has been diagnosed as suffering or from which a patient or subject is suspected to suffer.
  • the term "therapeutically effective” as used herein refers to a therapeutic agent or an amount of therapeutic agent that elicits a desirable biological activity or effect.
  • the term “therapeutically effective amount” as used herein refers to that amount of the therapeutic agent sufficient to result in partially or completely alleviating, inhibiting, ameliorating and/or relieving the condition, disease or disorder, or partially or completely alleviating, inhibiting, ameliorating and/or relieving the symptoms associated with the condition, disease or disorder.
  • the term refers to the amount of the therapeutic agent sufficient to result in partially or completely slowing the advancement of a condition, disease or disorder, and / or slowing the advancement of one or more of the symptoms associated with a condition, disease or disorder. In another embodiment, the term refers to the amount of therapeutic agent sufficient to cause regression of the condition, disease or disorder, and / or causing regression of one or more of the symptoms associated with the condition, disease or disorder. In another embodiment, the term refers to the amount of therapeutic agent sufficient to prevent the condition, disease or disorder, and / or to prevent one or more of the symptoms associated with the condition, disease or disorder. In another embodiment, the term refers to the amount of therapeutic agent sufficient to prevent the advancement of the condition, disease or disorder, and / or preventing the advancement of one or more of the symptoms associated with the condition, disease or disorder.
  • the terms “subject” or “patient” are used interchangeably and refer to mammals such as humans and non-human primates, as well as experimental animals such as rabbits, rats, and mice.
  • the subject or patient is a human.
  • the subject or patient is a male human.
  • the subject or patient is a female human. Accordingly, the term “subject” or “patient” as used herein means any mammalian patient or subject to which the compounds useful for the present invention can be administered.
  • routine screening methods are used to either identify and/or diagnose patients for treatment according to the methods of the invention; to identify the existence of a specific condition, disease or disorder which is associated with decreased expression of frataxin; to identify the existence of a specific condition, disease or disorder which is associated with a decreased level of frataxin; to determine risk factors associated with a targeted or suspected condition, disease or disorder; or to determine the status of an existing condition, disease or disorder in the subject.
  • routine screening methods include, but are not limited to, for example, conventional work-ups to determine risk factors that may be associated with the targeted or suspected condition, disease or disorder; conventional genetic screening methods and the like.
  • the subject is a patient diagnosed with a condition, disease or disorder, or symptoms associated with a condition, disease or disorder, which condition, disease or disorder is associated with decreased expression of frataxin.
  • the subject is a patient diagnosed with a condition, disease or disorder, or symptoms associated with a condition, disease or disorder, which condition, disease or disorder is associated with decreased expression of frataxin when compared to a healthy subject or patient.
  • the subject is a patient diagnosed with a condition, disease or disorder, or symptoms associated with a condition, disease or disorder, which condition, disease or disorder is associated with a decreased level of frataxin.
  • the subject is a patient diagnosed with a condition, disease or disorder, or symptoms associated with a condition, disease or disorder, which condition, disease or disorder is associated with a decreased level of frataxin when compared to a healthy subject or patient.
  • the subject is a patient diagnosed with a condition, disease or disorder, which condition, disease or disorder is associated with decreased frataxin expression, but which patient or subject is asymptomatic.
  • the subject is a patient diagnosed with a condition, disease or disorder, which condition, disease or disorder is associated with a decreased level of frataxin, but which patient or subject is asymptomatic.
  • the subject is a patient diagnosed with Friedreich's ataxia.
  • the subject is a patient diagnosed with Friedreich's ataxia but is asymptomatic. In one embodiment the subject is a patient diagnosed with Friedreich's ataxia with retained reflexes. In one embodiment the subject is a patient diagnosed with Friedreich's ataxia with retained reflexes but is asymptomatic. In one embodiment the subject is a patient diagnosed with late onset Friedreich's ataxia. In one embodiment the subject is a patient diagnosed with late onset Friedreich's ataxia but is asymptomatic. In one embodiment the subject is asymptomatic but has one or more genetic risk factors associated with a condition, disease or disorder, which condition, disease or disorder is associated with decreased frataxin expression.
  • the subject is asymptomatic but has one or more genetic risk factors associated with a condition, disease or disorder, which condition, disease or disorder is associated with a decreased level of frataxin. In one embodiment the subject is asymptomatic but has one or more genetic risk factors associated with Friedreich's ataxia. In one embodiment the subject is asymptomatic but is judged to be at high risk of developing a condition, disease or disorder associated with decreased frataxin expression. In one embodiment the subject is asymptomatic but is judged to be at high risk of developing a condition, disease or disorder associated with a decreased level of frataxin. In one embodiment the subject is asymptomatic but is judged to be at high risk of developing Friedreich's ataxia. In one embodiment the subject is asymptomatic but is judged to be a carrier of Friedreich's ataxia.
  • the patient or subject has been identified as having greater than about 75 unstable homozygous GAA trinucleotide repeat expansions in the intron- 1 on both of the alleles in the gene which encodes frataxin. In one embodiment the patient or subject has been identified as having greater than about 75 unstable homozygous GAA trinucleotide repeat expansions in the intron-1 on one of the alleles in the gene which encodes frataxin. In one embodiment the patient or subject has been identified as having between about 75 and about 300 GAA triplet repeat expansions in the intron-1 on both of the alleles in the gene which encodes frataxin.
  • the patient or subject has been identified as having between about 75 and about 300 GAA triplet repeat expansions in the intron-1 on one of the alleles in the gene which encodes frataxin. In one embodiment the patient or subject has been identified as having greater than about 300 GAA triplet repeat expansions in the intron-1 on both of the alleles in the gene which encodes frataxin. In one embodiment the patient or subject has been identified as having greater than about 300 GAA triplet repeat expansions in the intron-1 on one of the alleles in the gene which encodes frataxin. In one embodiment the subject or patient has been identified as being compound heterozygous for a GAA repeat expansion in the intron-1 of the gene which encodes frataxin and a point mutation or deletion.
  • the "patient” or “subject” with the condition, disease or disorder, or the symptoms associated with the condition, disease or disorder has either decreased frataxin expression or a decreased level of frataxin such that the residual cellular level of frataxin is from about 2% to about 30%; more typically from about 5% to about 25%; more typically from about 10% to about 20% of the residual cellular level of frataxin of a healthy counterpart.
  • the term “Friedreich's ataxia” shall be taken to mean an autosomal recessive congenital ataxia caused by a mutation(s) in the gene which encodes frataxin.
  • “Friedreich's ataxia” refers to a subject or patient who has been identified as having greater than about 300 unstable homozygous GAA trinucleotide repeat expansions in the intron-1 on both of the alleles in the gene which encodes frataxin.
  • “Friedreich's ataxia” refers to a subject or patient who has been identified as having late stage on-set of Friedreich's ataxia.
  • late stage on-set Friedreich's ataxia shall be taken to refer to a subject or patient who has greater than from about 75 to about 300 unstable homozygous GAA trinucleotide repeat expansion in the intron-1 on both of the alleles in the gene which encodes frataxin.
  • Friedreich's ataxia refers to a subject or patient who has been identified as a heterozygous carrier of Friedreich's ataxia.
  • a carrier of Friedreich's ataxia refers to a subject or patient who has greater than about 75 unstable homozygous GAA trinucleotide repeat expansion in the intron-1 on one of the alleles in the gene which encodes frataxin.
  • the subject or patient has been identified as being compound heterozygous for a GAA repeat expansion in the intron-1 of the gene which encodes frataxin and a point mutation or deletion.
  • the symptoms associated with the condition, disease or disorder are selected from the group consisting of muscle weakness in the arms and legs, loss of co-ordination, loss of deep tendon reflexes, loss of extensor plantar responses, loss of vibratory and proprioceptive sensation, vision impairment, involuntary and / or rapid eye movements, hearing impairment, slurred speech, curvature of the spine (scoliosis), high plantar arches (pes cavus deformity of the foot), carbohydrate intolerance, diabetes mellitus and heart disorders (including but not limited to atrial fibrillation, tachycardia (fast heart rate), hypertrophic cardiomyopathy, cardiomegaly, symmetrical hypertrophy, heart murmurs, and heart conduction defects).
  • the term "mammal” includes, but is not limited to mammals such as a human, a non-human primate, canine, feline, bovine, ovine, porcine, murine, or other veterinary or laboratory mammals such as rabbits, rats, and mice.
  • mammals such as a human, a non-human primate, canine, feline, bovine, ovine, porcine, murine, or other veterinary or laboratory mammals such as rabbits, rats, and mice.
  • a therapy which reduces the severity of pathology in one species of mammal is predictive of the effect of the therapy on another species of mammal.
  • the term “modulate” shall be taken to encompass either a decrease or an increase in the expression, level or activity depending on the target molecule.
  • the term "regulating the expression of” shall be taken to mean either an intervention which results in a decrease in the expression of the target molecule, or an intervention which results in an increase in the expression of the target molecule.
  • the regulation is an intervention which results in an "increase” or “up-regulation”, which terms are used herein interchangeably, and which, as used herein, shall be taken to mean resulting in, either directly or indirectly, an increase in the level of the target molcule expressed.
  • the term "increasing the expression of frataxin” shall be taken to mean that the cellular expression of frataxin precursor has, either directly or indirectly, been increased when compared to the cellular expression of frataxin precursor prior to treatment in accordance with the method of the invention. Without wishing to be bound by theory, it is thought that affecting an increase in the expression of frataxin precursor will result initially in an increase in the level of frataxin precursor which will in turn lead to an increase in the level of one or both of intermediate frataxin and mature frataxin as the frataxin precursor is further metabolized.
  • frataxin precursor is directly increased by modulation of the epigenetic state of the gene which encodes frataxin for example by either direct or indirect downstream modulation of P-TEFb and RNA polymerase II; by modulation of histone methylation; by modulation of transcriptional pause release; by relieving repression; or by modulating the methylation of CPG's in the DNA.
  • the expression of frataxin precursor is directly increased by the modulation of the epigenetic state via relieving heterochromatinisation.
  • the expression of frataxin precursor is modulated indirectly for example by inhibiting the expression of a negative regulator of frataxin, for example the negative anti-sense oligo repressor of expression FAST- 1 , or by inducing the expression of a positive regulator of frataxin.
  • a negative regulator of frataxin for example the negative anti-sense oligo repressor of expression FAST- 1
  • FAST- 1 the negative anti-sense oligo repressor of expression
  • FAST- 1 the expression of a positive regulator of frataxin.
  • epigenetic silencing in Friedreich's ataxia may be associated with depletion of CTCF (CCCTC-binding factor) and antisense transcription.
  • the term "increasing the level of frataxin” shall be taken to mean that the level of frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin, in a cell, subject or patient has, either directly or indirectly, been increased when compared to the level of frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin, in a cell subject or patient prior to treatment in accordance with the method of the invention.
  • one means for directly increasing the level of frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin, in a cell, subject or patient is to increase the expression of frataxin.
  • means for indirectly increasing the level of frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin, in a cell, subject or patient may include either increasing the stability of frataxin mRNA and / or decreasing the rate of degradation of frataxin, including frataxin precursor, intermediate frataxin, and / or mature frataxin.
  • the level of frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin is increased by at least about 1.5 fold when compared to the level of frataxin, including frataxin precursor, intermediate and / or mature frataxin in the cell, subject or patient prior to treatment in accordance with a method of the invention. In one embodiment the level of frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin, is increased by at least about 2 fold when compared to the level of frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin, in the cell, subject or patient prior to treatment in accordance with a method of the invention.
  • the level of frataxin including frataxin precursor, intermediate frataxin and / or mature frataxin, is increased by at least about 5 fold when compared to the level of frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin, in the cell, subject or patient prior to treatment in accordance with a method of the invention.
  • the level of frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin is measured as the steady state level after a period of treatment.
  • the level of frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin, in the cell, subject or patient treated in accordance with a method of the invention is increased to at least about 10% of the level of frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin, in a healthy cell or a healthy subject.
  • the level of frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin, in the cell, subject or patient treated in accordance with a method of the invention is increased to at least about 20% of the level of frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin, in a healthy cell or a healthy subject.
  • the level of frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin, in the cell, subject or patient treated in accordance with a method of the invention is increased to at least about 30% of the level of frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin, in a healthy cell or a healthy subject.
  • the level of frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin, in the cell, subject or patient treated in accordance with a method of the invention is increased to at least about 40% of the level of frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin, in a healthy cell or a healthy subject.
  • the level of frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin, in the cell, subject or patient treated in accordance with a method of the invention is increased to at least about 50% of the level of frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin, in a healthy cell or a healthy subject.
  • the level of frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin, in the cell, subject or patient treated in accordance with a method of the invention is increased to at least about 75% of the level of frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin, in a healthy cell or a healthy subject.
  • the level of frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin, in the cell, subject or patient treated in accordance with a method of the invention is increased to at least about 100% of the level of frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin, in a healthy cell or a healthy subject.
  • the level of frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin, in the cell, subject or patient treated in accordance with a method of the invention is increased to about that of a heterozygous carrier of Friedreich's ataxia.
  • the level of frataxin, including frataxin precursor, intermediate frataxin and/or mature frataxin, in the cell, subject or patient treated in accordance with a method of the invention is increased to more than about that of a heterozygous carrier of Friedreich's ataxia.
  • the level of frataxin, including frataxin precursor, intermediate frataxin and/or mature frataxin, in the cell, subject or patient treated in accordance with a method of the invention is increased to be about the same as that of a healthy cell or subject.
  • the level of frataxin, including frataxin precursor, intermediate frataxin and/or mature frataxin is measured as a steady state level achieved after a period of treatment.
  • the relative or absolute increase in level of frataxin is determined by comparing the total amount of frataxin, including frataxin precursor, intermediate frataxin and mature frataxin, present in the cell, subject, or patient before and after treatment in accordance with a method of the invention. In another embodiment, the relative or absolute increase in level of frataxin is determined by comparing the amount of mature frataxin present in the cell, subject, or patient before and after treatment in accordance with a method of the invention. In another embodiment, the relative or absolute increase in level of frataxin is determined by comparing the amount of frataxin precursor present in the cell, subject, or patient before and after treatment in accordance with a method of the invention.
  • the relative or absolute increase in the level of frataxin is achieved by an increase in the expression of frataxin and is determined by comparing the amount of frataxin precursor present in the cell, subject or patient before and after treatment in accordance with a method of the invention. In another embodiment, the relative or absolute increase in the level of frataxin is achieved by an increase in the expression of frataxin and is determined by comparing the amount of mature frataxin present in the cell, subject or patient before and after treatment in accordance with a method of the invention.
  • Non-limiting examples of useful increases in the levels of frataxin are provided.
  • a level of frataxin including frataxin precursor, intermediate frataxin and / or mature frataxin, of about 20% of the level of frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin, of that seen in a healthy cell or subject results in late onset of the condition, disease or disorder, or the symptoms associated with the condition, disease or disorder.
  • a method of the present invention results in an increase in the level of frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin, to greater than about 20% of the level in a healthy cell or subject
  • the increase in frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin is expected to slow the advancement of the condition, disease or disorder or the symptoms associated with the condition, disease or disorder.
  • a level of about 50% of the level of frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin, of that seen in a healthy cell or subject results in asymptomatic state.
  • a method of the present invention results in an increase in the level of frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin, to greater than about 50% of the level in a healthy cell or subject
  • the increase in frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin is expected to significantly slow the advancement of the condition, disease or disorder or the symptoms associated with the conditions, disorder or disease, and potentially even prevent further advancement or lead to regression of the condition disorder or disease, or the symptoms associated with the condition, disease or disorder.
  • health cell is taken to mean a cell taken from a "healthy subject”.
  • the term "healthy subject” shall be taken to mean a subject who has not been diagnosed with a condition, disease or disorder associated with decreased level of frataxin or with decreased expression of frataxin.
  • the healthy subject has been identified as not having Friedreich's ataxia.
  • the healthy subject has been identified as not having late onset Friedreich's ataxia.
  • the healthy subject has been identified as having less than about 75 unstable homozygous GAA trinucleotide repeat expansion in the intron-1 on both of the alleles in the gene which encodes frataxin.
  • the healthy subject has been identified as having less than about 25 unstable homozygous GAA trinucleotide repeat expansion in the intron-1 on both of the alleles in the gene which encodes frataxin. In one embodiment, the healthy subject has been identified as not having pathological mutations or repeat expansions on either allele of the intron-1 of the gene which encodes frataxin.
  • the term "decreased level of frataxin” shall be taken to mean that the level of frataxin, including frataxin precursor, intermediate frataxin and mature frataxin, present in a cell, subject or patient is lower than the level of frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin, observed in a healthy cell or subject.
  • the decreased level of frataxin refers to a decreased level of frataxin precursor.
  • the decreased level of frataxin refers to a decreased level of mature frataxin.
  • the term "decreased expression of frataxin” shall be taken to mean that the expression of frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin, in a cell, subject or patient is lower than the expression of frataxin, including frataxin precursor, intermediate frataxin and mature frataxin, observed in a healthy cell or subject.
  • the decreased expression of frataxin refers to a decreased expression of frataxin precursor.
  • the cells associated with the methods of the present invention are those where a decrease in frataxin expression or a decrease in the level of frataxin in one or more of these cell types is thought to contribute specifically, in whole or in part, to the in vivo pathology of the patient or subject with the condition, disease or disorder associated with decreased frataxin expression or a decreased level of frataxin, or the associated symptoms.
  • Such cells include, but are not limited to, cerebellar neurons, neurons of the spinal tract, dorsal root ganglia and sensory neurons, aural and optic nerves, cardiomyocytes, and / or cells of the pancreas including islets.
  • cellular pathways believed to be modulated by changes in levels of frataxin include, but are not limited to, pathways that rely on functionality of an iron-sulphur protein such as the enzyme aconitase in the Kreb's/TCA cycle; succinate dehydrogenase subunit B (SDHB) in the electron transport chain; DNA polymerases (Pol ⁇ , ⁇ and ⁇ ) and the major DNA mutagenesis enzyme Pol ⁇ important in DNA replication mechanisms and xanthine oxidase used in purine catabolism.
  • an iron-sulphur protein such as the enzyme aconitase in the Kreb's/TCA cycle
  • SDHB succinate dehydrogenase subunit B
  • the cells associated with the methods of the invention are obtained from, or are present in, a subject diagnosed with a condition, disease or disorder associated with decreased expression of frataxin. In one embodiment the cell is obtained from, or is present in, a subject diagnosed with a condition, disease or disorder associated with a decreased level of frataxin. In one embodiment the cell is obtained from, or is present in, a subject diagnosed with Friedreich's ataxia. In one embodiment the cell is obtained from, or is present in, a human subject diagnosed with Friedreich's ataxia.
  • the cell is obtained from, or is present in, a non-human species diagnosed with either a condition, disease or disorder associated with decreased expression of frataxin or condition, disease or disorder associated with a decreased level of frataxin or with Friedreich's ataxia, including genetic variants thereof.
  • the cell is in vivo.
  • the cell is ex vivo.
  • the cell is in vitro.
  • the term "frataxin” shall be taken to mean one or more of the precursor polypeptide, intermediate frataxin and mature frataxin and the frataxin encoding nucleotide sequence and post translationally modified protein or polypeptide polymorphic variants, spliced variants, alleles, mutants and interspecies homologs that: (1) have an amino acid sequence that has greater than about 90% amino acid sequence identity, for example 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or greater amino acid sequence identity, preferably over a region of at least about 25, 50, 100, 200, 300, 400 or more amino acids or over the full-length to an amino acid sequence encoded by frataxin nucleic acid or to an amino acid sequence encoded by a frataxin polypeptide; (2) bind to antibodies eg polyclonal antibodies, raised against an immunogen comprising an amino acid sequence encoded by a frataxin nucleic acid (eg frataxin polynucleot
  • the term "gene which encodes frataxin” refers to a genomic region that encodes frataxin protein and / or controls the transcription of frataxin mRNA.
  • the term shall be taken to encompass coding sequences as well as any non- coding elements, including but not limited to, promoters, enhancers, silencers, introns and 5' and 3' untranslated regions.
  • a gene which encodes frataxin may include flanking sequences 5' and / or 3' to a known annotated frataxin open reading frame, including, but not limited to, 1 Kb, 2Kb, 3Kb, 4Kb, 5Kb, 6Kb, 7Kb, 8Kb, 9Kb, and / or 10Kb, or more flanking the 5' and / or 3' end of a known annotated frataxin open reading frame.
  • a gene which encodes frataxin may be a human gene which encodes frataxin.
  • a gene which encodes frataxin may be a corresponding homolog for a gene which encodes frataxin in a different species, including, but not limited to, for example a mouse.
  • Methods are available in the art for determining the level of frataxin, including frataxin precursor, intermediate frataxin and / or mature frataxin for example routine methods such as Western Blot analysis or commercially available dip stick testing kits such as those available from Abeam ® or Mitosciences ® .
  • Methods are available in the art for the identification of conditions, diseases or disorders associated with a decreased expression of frataxin; conditions, diseases or disorders associated with a decreased level of frataxin; for the identification of GAA triplet repeat expansions on the intron-1 of the gene which encodes frataxin; and / or which identify a point mutation or deletion on the gene which encodes frataxin including methods for the diagnosis of Friedreich's ataxia, for example the Friedreich's ataxia repeat expansion test available from Athena Diagnostics ® .
  • BET-family bromodomain refers to members of the bromodomain family of proteins which contain two N-terminal bromodomains. This family includes bromodomain members known as BRD2, BRD3, BRD4 and BRDT. These bromodomains are well known to share a common domain architecture featuring two amino-terminal bromodomains which exhibit high levels of sequence conservation, and a more divergent carboxy terminal recruitment domain.
  • BET4 refers to BET-family bromodomain-containing protein 4, which is a member of the BET bromodomain family.
  • BET-family bromodomain inhibitor shall be taken to mean a compound which shows inhibitory activity at one or more of the BET-family bromodomains, including by preventing the bromodomain from binding to acetyl- modified histone tails.
  • the "BET-family bromodomain inhibitor” is a BRD4 inhibitor.
  • the "BET-family bromodomain inhibitor” is a compound which inhibits bromodomain 1 of BRD4.
  • the "BET-family bromodomain inhibitor” is a compound which inhibits bromodomain 2 of BRD4.
  • the "BET-family bromodomain inhibitor” is a compound which inhibits both bromodomain 1 and bromodomain 2 of BRD4. Routine methods are available in the art to determine BET-family bromodomain activity such as the fluorescence binding assay disclosed herein and others.
  • IC50 refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response in an assay that measures such response. The value depends on the assay used.
  • other therapeutic agents refers to any therapeutic agent that has been used, is currently used or is known to be useful for treating a disease or a disorder encompassed by the present invention.
  • the pharmaceutical methods and associated methods of treatment and pharmaceutical compositions of the present invention utilize BET-family bromodomain inhibitors, or a pharmaceutically acceptable salt thereof.
  • Bromodomain-containing proteins are known to be of substantial biological interest, as components of transcription factor complexes and determinants of epigenetic memory.
  • the BET-fami!y (BRD2, BRD3, BRD4 and BRDT) shares a common domain architecture featuring two amino-terminal bromodomains that exhibit high levels of sequence conservation, and a more divergent carboxy-terminal recruitment domain (Filippakopou!os, P, et al., Nature 2010, 468, 1067-1073, incorporated by reference herein in its entirety for all purposes).
  • BRD2 and BRD3 are reported to associate with histones along actively transcribed genes and may be involved in facilitating transcriptional elongation (Leroy et al, Mol. Cell.
  • BRD4 or BRD3 may fuse with NUT (nuclear protein in testis) forming novel fusion oncogenes, BRD4-NUT or BRD3-NUT, in a highly malignant form of epithelial neoplasia (French et al. Cancer Res., 2003, 63, 304-307 and French et al. J. Clin. Oncol. 2004, 22, 4135-4139, both of which are incorporated by reference herein in their entirety for all purposes).
  • NUT nuclear protein in testis
  • BRDT is believed to be uniquely expressed in the testes and ovary. All family members have been reported to have some function in controlling or executing aspects of the cell cycle, and have been shown to remain in complex with chromosomes during cell division— suggesting a role in the maintenance of epigenetic memory. In addition some viruses make use of these proteins to tether their genomes to the host cell chromatin, as part of the process of viral replication (You et al. Cell 2004 117, 349-60, incorporated by reference herein in its entirety for all purposes).
  • BRD4 appears to be involved in the recruitment of the pTEF-P complex to inducible genes, resulting in phosphorylation of RNA polymerase and increased transcriptional output (Hargreaves et al. Cell 2009 138, 129-145, incorporated by reference herein in its entirety for all purposes).
  • Bromodomain-containing protein 4 is a member of the BET-family that in yeast and animals contains two tandem bromodomains (BDI and BDII) and an extraterminal (ET) domain.
  • BRD4 is a double bromodomain-containing protein that binds preferentially to acetylated chromatin.
  • four BET proteins (BRD2, BRD3, BRD4 and BRDT) exhibit similar gene arrangements, domain organizations, and some functional properties (Wu, S. et al. J. Biol. Chem. 2007, 282, 13141-13145, incorporated by reference herein in its entirety for all purposes).
  • Small molecule BET-family bromodomain inhibitors have been described with a wide variety of different chemical scaffolds and different chemotype approaches are known to be useful (see for example Gamier et al. Expert Opinion Ther Patents 2014, 24(2), 185-199; Hewings et al. J Med Chem 2012, 55, 9393-413; and Owen et al. Drug Disco Today: Technologies 2012, 10, 1016, all of which are incorporated by reference herein in their entirety for ail purposes). To date, small molecule BET-family bromodomain inhibitors have been mainly reported as being useful for treatment inflammatory diseases and / or various cancers, but some have also been reported to be useful for the treatment of cardiovascular diseases and to treat male fertility.
  • BET-family bromodomain inhibitors can be identified using routine methods available in the art such as the fluorescence polarization (FP) binding assay disclosed herein.
  • the BET-family bromodomain inhibitors useful in the present invention have an activity of about ⁇ 5 ⁇ in the fluorescence polarization (FP) binding assay at either bromodomain 1 , bromodomain 2 or both bromodomain 1 and 2.
  • the BET-family bromodomain inhibitors useful in the present invention have an activity of about ⁇ 2 ⁇ in the fluorescence polarization (FP) binding assay disclosed herein at either bromodomain 1 , bromodomain 2 or both bromodomain 1 and 2.
  • the BET-family bromodomain inhibitors useful in the present invention have an activity of about ⁇ 1 ⁇ in the fluorescence polarization (FP) binding assay disclosed herein at either bromodomain 1 , bromodomain 2 or both bromodomain 1 and 2.
  • FP fluorescence polarization
  • BET-family bromodomain inhibitors useful in the present invention include, but are not limited to compounds described below, including those which are in clinical development.
  • I-BET762 is reported to be in clinical development for the treatment of various indications including acute & chronic lymphocytic leukemia; acute & chronic myelogenous leukemia; Hodgkin's & Non-Hodgkin's lymphoma; multiple myeloma; myeloproliferative neoplasms; NUT mideline carcinoma; hematological carcinoma & solid tumors; and atherosclerosis.
  • I-BET762 and analogues thereof include those described in International Patent application number PCT/EP2010/066697, published as WO2011/054845 on 12 th May 2011 ; International Patent application number PCT/EP2010/066696,published as WO201 1/054844 on 12 th May 201 1 ; International Patent application number PCT/EP2011/060179, published as WO2011/161031 on 29 th December 201 1 ; and Nicodeme E et al. Nature, 2010, 468, 1 119-23, all of which are incorporated by reference herein in their entirety for ail purposes.
  • JQ-1 and analogues thereof include those described in International Patent application number PCT/US201 1/036647, published as WO2011/143651 on 17 th November 2011 ; International Patent application number PCT/US2011/036667, published as WO2011/143657 on 17 th November 2011 ; International Patent application number PCT/US201 1/036672, published as WO2011/143660 on 17 th November 201 1 ; and Filippakopoulos P et al. Nature, 2010, 468, 1067-73, all of which are incorporated by reference herein in their entirety for all purposes.
  • CPI-203 has since been reported to have BRD4 activity (Devaiah, B. N. et al. Proc Natl Acad Sci USA 2012, 109(18), 6927-32, which is incorporated by reference herein in its entirety for all purposes) and is reported to be in preclinical development for a variety of indications including cancer; hematological cancer; lymphoma; and Non-Hodgkin's lymphoma.
  • OTX015 is reported to be in clinical development for various indications including leukemia; cancer; Crohn's disease; ulcerative colitis; hematological cancer; acute lymphocytic leukemia; acute myelogenous leukemia; Non-Hodgkin's lymphoma; multiple myeloma; and breast, lung, non-small cell, pancreas, prostate tumors. Further related compounds with this chemical scaffold are described in International Patent application PCT/JP2006/310709, published as WO2006/129623 on 7 th December 2006; and International Patent application PCT/JP2008/-73864, published as WO 2009/084693 on 9 th July 2009, both of which are incorporated by reference herein in their entirety for all purposes.
  • GW-841819X is reported to be in preclinical development for various indications including dyslipidemia; cancer; and hematological neoplasm.
  • CPI-0610 is reported to be in clinical development for various indications including Hodgkin's & Non-Hodgkin's lymphoma; multiple myeloma; acute lymphocytic leukemia; acute and chronic myelogenous leukemia; myelodysplasia syndrome; and myeloproliferative neoplasms.
  • BET-BAY-002 is reported to be in preclinical development for various indications including cancer.
  • l-BET-151 is reported to be in preclinical development for various indications including leukemia; cancer; mixed lineage leukemia; hematological cancer; bone resorprtion; and inflammatory disease.
  • RVX-208 is reported to be in clinical development for various indications including atherosclerosis; diabetes; acute coronary syndrome; myocardial Infarction; Alzheimer's disease; stroke; mild cognitive impairment; low HDL cholesterol; and immunological diseases.
  • l-BET-726 is reported to be in preclinical development for various indications including cancer.
  • SRX-2523 is reported to be in preclinical development for various indications including cancer and hematological neoplasm.
  • BET-family bromodomain inhibitors disclosed therein include N-(2-hydroxy-3- methylquinolin-6-yl)piperidine-1-sulfonamide
  • BET-family bromodomain inhibitors disclosed therein include N-[4-(2,4- difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1 H-pyrrolo[2,3-c]pyridin- 4- yl)phenyl]ethanesulfonamide:
  • BET-family bromodomain inhibitors which are useful for the methods disclosed herein include, but are not limited to, the following BET-family bromodomain inhibitors which have been disclosed in the public domain as being in preclinical or clinical development BMS-986158 (Bristol Myers Squibb); RVX-297 (Resverlogix); RVS-2135 (Resverlogix); ZEN-3365 (Zenith); ZEN-31 18 (Zenith); KM-601 (Kainos); SF- 2535 (Signal Rx); AU-004 (Aurigene, Orion); ABBV-075 (Abbvie); TEN-010 (Tensha Therapeutics); and BAY1238097 (Bayer).
  • BET-family bromodomain inhibitors which are useful for the methods described herein include, but are not limited to, compounds disclosed in the following international patent applications: triazolodiazepine derivatives disclosed in International Patent application PCT/US2012/036569, published as WO 2012/151512 on 8 th November 2012; tetrahydroquinoline derivatives disclosed in International Patent application PCT/EP2010/066701 , published as WO 2011/054848 on 12 th May 2011 ; imidazoquinoline derivatives disclosed in International patent application PCT/EP2010/066699, published as WO 201 1/054846 on 12 th May 201 1 ; quinazolinone derivatives disclosed in International Patent application PCT/US2009/048457, published as WO 2009/158404 on 30 th December 2009; quinazolinone derivatives disclosed in International Patent application PCT/US2010/031870, published as WO 2010/123975 on 28 October 2010; triazolopyridazine-6-amine derivatives disclosed in International Patent application PCT
  • BET -family bromodomain inhibitors suitable for use with the methods of the present invention include those described in US provisional patent application serial number 62/181281 , which was filed on 18 th June 2015 which is incorporated by reference herein in its entirety for all purposes.
  • This disclosure includes compounds of Formula I:
  • 4 to 7 membered heterocyclyl optionally substituted with one, two, three or four E, which said 4 to 7 membered heterocyclyl comprises one or two heteroatoms independently selected for each occurrence from the group of N, O and S;
  • R 1A is selected from the group consisting of
  • R 1 B is selected from the group consisting of
  • R 1 C is selected from the group consisting of
  • R 2A is selected from the group consisting of
  • R 2B is selected from the group consisting of (i) -d-Cealkyl optionally substituted with one, two, three or four G;
  • Ci-Cealkyl is optionally substituted with one, two, three or four G;
  • W is selected from the group consisting of:
  • Y is selected from the group consisting of:
  • R 3 is selected from the group consisting of:
  • R 4A is selected from the group consisting of
  • Ci-C 3 alkyl optionally substituted with one, two, three or four G;
  • Ci-C 3 alkyl optionally substituted with one, two, three or four G;
  • - F is independently selected for each occurrence from the group consisting of - F, -CI, -OH, -CN, -CH 3 , -CH 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CF 2 CF 3 , -CH 2 OH, - OCH 3 , -OCH2F, -OCHF2, -OCF3, -SCH3, -SCH 2 F, -SCHF2, -SCF3 -NH 2 , - NH(CH 3 ), and -N(CH 3 ) 2 ;
  • E is independently selected for each occurrence from the group consisting of:
  • G is independently selected for each occurrence from the group consisting of
  • J is independently selected for each occurrence from the group consisting of -H, -F, -CI, -OH, -CN, -CH 3 , -CH2CH3, -CH2F, -CHF2, -CF 3 , -CF 2 CF 3 , -CH 2 OH, - OCH3, -OCH2F, -OCHF2, -OCF3, -SCH3, -SCH 2 F, -SCHF2, -SCF3 -NH 2 , - NH(CH 3 ), and -N(CH 3 ) 2 .
  • R 1A is selected from the group consisting of -CH 2 OCH 3 ; phenyl; methoxyphenyl; and pyridyl;
  • R 1 B is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, and
  • R 1 C is -H
  • R 2A is selected from the group consisting of -CH3;
  • R 2B is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, and
  • Y is selected from the group consisting of -CH 2 - and -CH 2 CH 2 -;
  • R 3 is -H
  • R 4A is selected from the group consisting of -CH 3 ; -C0 2 H; and -C(0)NHCH 3 ;
  • R 10 is -H, or a pharmaceutically acceptable salt thereof.
  • BET-family bromodomain inhibitors including their methods of preparation, described in US provisional patent application serial number 62/181281 , which was filed on 18 th June 2015, include:
  • Preferred BET-family bromodomain inhibitors described in US provisional patent application serial number 62/181281 , which was filed on 18 th June 2015, include:
  • BET -family bromodomain inhibitors suitable for use with the methods of the present invention include those described in US provisional patent application serial number 62/181281 , which was filed on 18 th June 2015 the disclosure of which is hereby incorporated by reference in its entirety for all purposes.
  • This disclosure includes compounds of Formula II:
  • R 1 is selected from the group consisting of:
  • R 1A is selected from the group consisting of
  • R 1 B is selected from the group consisting of
  • R 1 C is selected from the group consisting of
  • W is selected from the group consisting of:
  • Y is selected from the group consisting of: (i) -CH 2 - optionally substituted with one or two J;
  • R 3 is selected from the group consisting of:
  • R 4A is selected from the group consisting of
  • Ci-C 3 alkyl optionally substituted with one, two, three or four G;
  • Ci-C 3 alkyl optionally substituted with one, two, three or four G;
  • 5 to 6 membered heteroaryl optionally substituted with one, two, three or four G, which said 5 to 6 membered heteroaryl ring comprises one, two, three or four heteroatoms independently selected for each occurrence from the group consisting of N, O and R 10 is independently selected for each occurrence from the group consisting of - H, -F, -CI, -OH, -CN, -CH 3 , -CH 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CF 2 CF 3 , -CH 2 OH, - OCH 3 , -OCH 2 F, -OCHF 2 , -OCF 3 , -SCH 3 , -SCH 2 F, -SCHF 2 , -SCF 3 -NH 2 , - NH(CH 3 ), and -N(CH 3 ) 2 ;
  • E is independently selected for each occurrence from the group consisting of:
  • G is independently selected for each occurrence from the group consisting of (i) -OH
  • J is independently selected for each occurrence from the group consisting of -H, -F, -CI, -OH, -CN, -CH 3 , -CH 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CF 2 CF 3 , -CH 2 OH, - OCH3, -OCH2F, -OCHF2, -OCF3, -SCH3, -SCH2F, -SCHF2, -SCF3 -NH 2 , - NH(CH 3 ), and -N(CH 3 ) 2 .
  • R 1A is selected from the group consisting of -CH 2 OCH 3 ; phenyl; methoxyphenyl; and pyridyl;
  • R 1 B is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, and
  • R 1 C is -H
  • Y is selected from the group consisting of -CH 2 - and -CH 2 CH 2 -;
  • R 3 is -H
  • R 4A is selected from the group consisting of -CH 3 ; -C0 2 H; and -C(0)NHCH 3 ;
  • R 10 is -H, or a pharmaceutically acceptable salt thereof.
  • BET-family bromodomain inhibitors including their methods of preparation, of Formula II described in US provisional patent application serial number 62/181281 , which was filed on 18 th June 2015 include: 6-(3,5-dimethyl-1 ,2-oxazol-4-yl)-4-[(1 S)-1-(2-methoxyphenyl)ethyl]-2- ⁇ [2-(morpholin-4- yl)ethyl]amino ⁇ pyrido[2,3-b]pyrazin-3(4H)-one;
  • alkyl whether used alone or as part of a substituent group refers to a saturated straight or branched hydrocarbon chain (ie a substituent obtained from a hydrocarbon by removal of a hydrogen) having from one to twenty carbon atoms or any number within this range, for example, from one to six carbon atoms, from one to four carbon atoms or from one to three carbon atoms.
  • Designated numbers of carbon atoms e.g. Ci- ⁇ shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger alkyl-containing substituent.
  • alkyl groups include, but are not limited to, methyl, ethyl, n- propyl, / ' so-propyl, n-butyl, sec-butyl, / ' so-butyl, te/f-butyl, pentyl, isoamyl, hexyl and the like. Where so indicated, alkyl groups can be optionally substituted. In substituent groups with multiple alkyl groups such as N(Ci-C 6 alkyl) 2 , the alkyl groups may be the same or different.
  • alkoxy refers to groups of formula - Oalkyl, wherein “alkyl” is as defined herein.
  • Designated numbers of carbon atoms e.g. -OC1-C6 shall refer independently to the number of carbon atoms in the alkyl moiety of the alkoxy group, for example, but not limited to, from one to six carbon atoms or from one to three carbon atoms.
  • Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, / ' so-propoxy, n-butoxy, sec-butoxy, /so-butoxy, te/f-butoxy, and the like. Where so indicated, alkoxy groups can be optionally substituted.
  • aryl whether used alone or part of another group refers to a carbocyclic fully unsaturated or partially unsaturated single or fused ring system. If the rings are fused, one of the rings must be fully unsaturated or partially unsaturated and the fused ring(s) may be fully saturated, partially unsaturated or fully unsaturated.
  • the aryl group may be optionally substituted as defined herein.
  • aryl embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, benzo[b][1 ,4]oxazin-3(4H)-onyl, 2,3-dihydro-1/-/ indenyl and 1 ,2,3,4- tetrahydronaphthalenyl.
  • cycloalkyl refers to a fully saturated hydrocarbon ring having from three to fourteen ring carbon atoms, for example, from four to seven; or from three to seven; or from three to six; or from three to five ring carbon atoms.
  • Cycloalkyl groups can be monocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fused, bridged, and/or spiro ring systems), wherein the carbon atoms are located inside or outside of the ring system. Any suitable ring position of the cycloalkyl group can be covalently linked to the defined chemical structure.
  • cycloalkyl rings can be optionally substituted.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctanyl, decalinyl.
  • cycloalkyl also includes carbocyclic rings which are bicyclic hydrocarbon rings, non- limiting examples of which include, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, 1 ,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.
  • haloalkyl and haloalkoxy are intended to include both branched and straight-chain saturated aliphatic “alkyl” or “alkoxy” groups respectively, wherein “alkyl” and “alkoxy” are as defined herein, having the specified number of carbon atoms and in which at least one hydrogen is replaced with a halogen atom.
  • halogen atom refers to F, CI, Br and I.
  • Haloalkyl groups include perhaloalkyl groups, wherein all hydrogens of an alkyl group have been replaced with halogens (e.g., -CF3, -CF2CF3).
  • halogen atoms can be the same (e.g. , CHF 2 , -CF 3 ) or different (e.g. , CF 2 CI).
  • haloalkyl or haloalkoxy groups can optionally be substituted with one or more substituents in addition to halogen.
  • haloalkyl groups include, but are not limited to, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl groups.
  • heterocyclyl and “heterocycloalkyl” are used interchangeably and, whether used alone or as part of another group, are defined herein as referring to a group having one or more rings (e.g., 1 , 2 or 3 rings) and having from 3 to 1 1 ring atoms (e.g.
  • ring atoms 3 to 6 ring atoms, 4 to 7 ring atoms, 4 to 5 ring atoms) wherein at least one ring atom, alternatively 1 to 5 ring atoms, alternatively 1 to 4 ring atoms, alternatively 1 to 3 ring atoms, alternatively one ring atom, alternatively two ring atoms, is a heteroatom, independently selected, unless indicated otherwise, from the group consisting of nitrogen (N), oxygen (O), and sulfur (S), and wherein the ring that includes the heteroatom is fully saturated.
  • N nitrogen
  • O oxygen
  • S sulfur
  • Exemplary heterocyclyl groups have from 3 to 1 1 ring atoms, alternatively 4 to 7 ring atoms, alternatively 4 to 5 ring atoms, alternatively 3 to 6 ring atoms, of which, where chemically possible, from 1 to 5, alternatively 1 to 4, alternatively 1 to 3, alternatively 4, alternatively 3, alternatively 2, alternatively 1 ring atom, is a heteroatoms independently selected in each instance from, unless indicated otherwise, the group consisting of nitrogen (N), oxygen (O), or sulfur (S).
  • N nitrogen
  • O oxygen
  • S sulfur
  • the ring atom of the heterocyclyl substituent that is bound to the group may be one of the heteroatoms, or it may be a ring carbon atom, where the ring carbon atom may be in the same ring as the heteroatom(s), or the ring carbon may be in a different ring from the heteroatom(s).
  • the heterocyclyl substituent can be optionally further substituted with one or more group(s) or substituent(s), which group(s) or substituent(s) may be bound to the heteroatom(s) or may be bound to the ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring rom the heteroatom(s).
  • Examples of monocyclic heterocyclyl groups include, but are not limited to, oxetanyl, diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyl oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl (valerolactam), 2,3,4,5-tetrahydro-1 /-/-azepinyl, 2, 3-dihydro-1 /-/-indo
  • heteroaryl is defined herein as a single or fused ring system having from five to eleven ring atoms (e.g. from five to ten ring atoms of from five to six ring atoms) wherein at least one ring atom, alternatively 2 ring atoms, alternatively 3 ring atoms, alternatively 4 ring atoms, in at least one ring is a heteroatom independently selected in each instance from, unless otherwise indicated, the group consisting of nitrogen (N), oxygen (O), and sulfur (S), and wherein further at least one of the rings comprising a heteroatom is fully unsaturated or partially unsaturated.
  • N nitrogen
  • O oxygen
  • S sulfur
  • heteroaryl groups that include 2 or more fused rings
  • additional rings may bear one or more heteroatoms, may be a carbocycle (e.g., 6,7-Dihydro-5/-/-cyclopentapyrimidine) or may be aryl (e.g., benzofuranyl, benzo-thiophenyl, indolyl, indolinyl, tetrahydroquinolinyl, chromanyl, 1 ,4-dioxochromanyl).
  • carbocycle e.g., 6,7-Dihydro-5/-/-cyclopentapyrimidine
  • aryl e.g., benzofuranyl, benzo-thiophenyl, indolyl, indolinyl, tetrahydroquinolinyl, chromanyl, 1 ,4-dioxochromanyl
  • the ring atom of the heteroaryl substituent that is bound to the group may be the at least one heteroatom, or it may be a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon may be in a different ring from the at least one heteroatom.
  • heteroaryl groups can be substituted.
  • the group or substituent may be bound to the heteroatom, or it may be bound to a ring carbon atom, where the ring carbon atom may be in the same ring as the heteroatom(s), or where the ring carbon atom may be in a different ring from the heteroatom(s).
  • Examples of monocyclic heteroaryl rings include, but are not limited to, 1 ,2,3,4-tetrazolyl, [1 ,2,3]triazolyl, [1 ,2,4]triazolyl, triazinyl, thiazol- 2-yl, thiazol-4-yl, imidazol-1-yl, 1/-/-imidazol-2-yl, 1/-/-imidazol-4-yl, oxazolyl, isoxazolin- 5-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazinyl, pyrazinyl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl pyridinyl.
  • heteroaryl rings containing 2 or more fused rings include, but are not limited to, benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, cinnolinyl, naphthyridinyl, benzimidazolyl, aza-indolyl, aza-benzimidazolyl, phenanthridinyl, 7/-/-purinyl, 9/-/-purinyl, 5/-/-pyrrolo[3,2-c]pyrimidinyl, 7/-/-pyrrolo[2,3- cflpyrimidinyl, pyrido[2,3-d]pyrimidinyl, 2-phenylbenzo[d]thiazolyl, 1 - -indolyl, 4,5,6,7- tetrahydro-1-/-/-indolyl, quinoxalinyl, 5-methylquinoxalinyl, quin
  • heteroaryl also includes pyridyl N-oxides and groups containing a pyridine N-oxide ring.
  • amino refers to -NH 2 .
  • alkylamino refers to - N(H)alkyl, the term “alkyl” having already been defined herein.
  • alkylamino substituents include, but are not limited to, methylamino, ethylamino, and propylamino.
  • dialkylamino refers to -
  • dialkylamino substituents include, but are not limited to, dimethylamino, diethylamino, ethylmethylamino, and dipropylamino.
  • hydroxy and “hydroxyl” are used interchangeably and as used herein mean an -OH group.
  • hydroxyalkyl and hydroxyalkoxy are intended to include both branched and straight-chain saturated aliphatic “alkyl” or “alkoxy” groups respectively, wherein “alkyl” and “alkoxy” are as defined herein, having the specified number of carbon atoms and in which at least one hydrogen is replaced with a -OH group.
  • hydroxyalkyl and hydroxyalkoxy groups can optionally be substituted with one or more substituents in addition to -OH. Examples of hydroxyalkyl groups include, but are not limited to, CH 2 OH, CH 2 CH 2 OH, CH 2 (OH)CH 2 OH.
  • sulfonyl refers to -S0 2 -.
  • substituted is used throughout the specification.
  • the term “substituted” is defined herein as a moiety, whether acyclic or cyclic, which has one or more (e.g. 1-10) hydrogen atoms replaced by a substituent as defined herein below.
  • Substituents include those that are capable of replacing one or two hydrogen atoms of a single moiety at a time, and also those that can replace two hydrogen atoms on two adjacent carbons to form said substituent.
  • substituents that replace single hydrogen atoms include, but are not limited to, halogen, hydroxy, and the like.
  • a two hydrogen atom replacement includes, but is not limited to, carbonyl, oximino, and the like.
  • Substituents that replace two hydrogen atoms from adjacent carbon atoms include, but are not limited to, epoxy, and the like.
  • any number of its hydrogen atoms can be replaced, as described above.
  • difluoromethyl is a substituted Ci alkyl
  • trifluoromethyl is a substituted Ci alkyl
  • 4-hydroxyphenyl is a substituted aryl ring
  • (N,N-dimethyl-5- amino)octanyl is a substituted Cs alkyl
  • 3-guanidinopropyl is a substituted C3 alkyl
  • 2-carboxy-3-fluoropyridinyl is a substituted heteroaryl.
  • a multi-moiety substituent is bound through the atom indicated by To illustrate this the term "-OCrCahydroxyalkyl” is an Od-Caalkyl group substituted by a hydroxy group. Further, any carbon number pre-fix attached to a multi-moiety substituent only applies to the moiety it immediately precedes. To illustrate, the term "cycloalkyl(Ci-C- alky contains two moieties: alkyl and cycloalkyl.
  • the (C 1 -C4) pre-fix on the cycloalkyl(Ci-C4)alkyl means that the alkyl moiety of the alkylcycloalkyl contains from 1 to 4 carbon atoms, the (C 1 -C4) pre-fix does not describe the cycloalkyl moiety.
  • a group of substituents are collectively described as being optionally substituted by one or more of a list of substituents, the group may include (1) unsubstitutable substituents, (2) substitutable substituents that are not substituted by the optional substituents, and / or (3) substitutable substituents that are substituted by one or more of the optional substituents.
  • a substituent such that it "may be substituted” or as being “optionally substituted” with up to a particular number of non-hydrogen substituents, that substituent may be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen substituents or by up to the maximum number of substitutable positions on the substituents, whichever is less.
  • a substituent is described as a heteroaryl optionally substituted with one, two or three substituents, then any heteroaryl with less than three substitutable positions would be optionally substituted by up to only as many non-hydrogen substituents as the heteroaryl has substitutable positions.
  • tetrazolyl which has only one substitutable position
  • C -6 alkyl is specifically intended to individually disclose Ci , C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3- C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.
  • Ci -3 alkyl is specifically intended to individually disclose Ci , C2, C3, C1-C3, C1-C2, and C2-C3 alkyl.
  • the BET-family bromodomain inhibitor is l-BET-762, or a pharmaceutically acceptable salt thereof.
  • the BET-family bromodomain inhibitor is JQ-1 , or a pharmaceutically acceptable salt thereof.
  • the BET-family bromodomain inhibitor is JQ-1 (+), or a pharmaceutically acceptable salt thereof. In one embodiment of the present invention BET-family bromodomain inhibitor is CPI-203, or a pharmaceutically acceptable salt thereof.
  • the BET-family bromodomain inhibitor is OTX-015, or a pharmaceutically acceptable salt thereof.
  • the BET-family bromodomain inhibitor is GW-841819X, or a pharmaceutically acceptable salt thereof.
  • the BET-family bromodomain inhibitor is CP-0610, or a pharmaceutically acceptable salt thereof.
  • the BET-family bromodomain inhibitor is CPI-232, or a pharmaceutically acceptable salt thereof.
  • the BET-family bromodomain inhibitor is BET-BAY-002, or a pharmaceutically acceptable salt thereof.
  • the BET-family bromodomain inhibitor is RVX-208, or a pharmaceutically acceptable salt thereof.
  • the BET-family bromodomain inhibitor is l-BET-726, or a pharmaceutically acceptable salt thereof.
  • the BET-family bromodomain inhibitor is SRX-2523, or a pharmaceutically acceptable salt thereof.
  • the BET-family bromodomain inhibitor is B S-988158, or a pharmaceutically acceptable salt thereof.
  • the BET-family bromodomain inhibitor is RVX-297, or a pharmaceutically acceptable salt thereof.
  • the BET-family bromodomain inhibitor is RVS-2135, or a pharmaceutically acceptable salt thereof.
  • the BET-family bromodomain inhibitor is ZEN-3365, or a pharmaceutically acceptable salt thereof.
  • the BET-family bromodomain inhibitor is ZEN-31 18, or a pharmaceutically acceptable salt thereof.
  • the BET-family bromodomain inhibitor is KM-601 , or a pharmaceutically acceptable salt thereof. In one embodiment of the present invention the BET-family bromodomain inhibitor is SF-2535, or a pharmaceutically acceptable salt thereof.
  • the BET-family bromodomain inhibitor is AU-004, or a pharmaceutically acceptable salt thereof.
  • the BET-family bromodomain inhibitor is ABBV-075, or a pharmaceutically acceptable salt thereof.
  • the BET-family bromodomain inhibitor is TEN-010, or a pharmaceutically acceptable salt thereof.
  • the BET-family bromodomain inhibitor is BAY1238097, or a pharmaceutically acceptable salt thereof.
  • the BET-family bromodomain inhibitor is N-(2-hydroxy-3-methylquinolin-6-yl)piperidine-1-sulfonamide, or a pharmaceutically acceptable salt thereof.
  • the BET-family bromodomain inhibitor is N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1 H-pyrrolo[2,3- c]pyridin- 4-yl)phenyl]ethanesulfonamide, or a pharmaceutically acceptable salt thereof.
  • the BET-family bromodomain inhibitor is N- ⁇ 6-[methyl(propanoyl)amino]-3-oxo-4-[(1S)-1-phenylpropyl]-3,4- dihydropyrido[2,3 b]pyrazin-2-yl ⁇ -beta-alanine, or a pharmaceutically acceptable salt thereof.
  • solvate means a physical association of a compound with one or more solvent molecules, whether organic or inorganic, including water ('hydrate').
  • solvent or water When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity.
  • the solvent or water When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
  • a salt of the compound may be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable solubility in water or oil.
  • a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound.
  • a salt is intended to be administered to a patient (as opposed to, for example, being used in an in vitro context)
  • the salt preferably is pharmaceutically acceptable.
  • pharmaceutically acceptable salt refers to a salt prepared by combining a compound useful for the invention (e.g. a compound of Formula (I)) with an acid whose anion, or a base whose cation, is generally considered suitable for human consumption.
  • Pharmaceutically acceptable salts are particularly useful as products of the methods of the present invention because of their greater aqueous solubility relative to the parent compound.
  • salts of the compounds useful for this invention are non-toxic "pharmaceutically acceptable salts.”
  • Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
  • suitable pharmaceutically acceptable acid addition salts of the compounds useful for the present invention include those derived from inorganic acids, such as hydrochloric, hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids.
  • Suitable organic acids generally include but are not limited to aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids.
  • suitable organic acids include but are not limited to acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, stearate, salicylate, p- hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2- hydroxyethanesulfonate, sufanilate, cyclohexylaminosulfonate, algenic acid, .beta.- hydroxybutyric acid, galactarate, galacturonate, adipate, alginate,
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, i.e., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts.
  • base salts are formed from bases which form non-toxic salts, including aluminum, arginine, benzathine, choline, diethylamine, diolamine, glycine, lysine, meglumine, olamine, tromethamine and zinc salts.
  • Organic salts may be made from secondary, tertiary or quaternary amine salts, such as tromethamine, diethylamine, ⁇ , ⁇ '-benzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.
  • secondary, tertiary or quaternary amine salts such as tromethamine, diethylamine, ⁇ , ⁇ '-benzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.
  • Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl (C.sub.1-C.sub.6) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (i.e., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (i.e., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (i.e., benzyl and phenethyl bromides), and others.
  • lower alkyl (C.sub.1-C.sub.6) halides e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides
  • dialkyl sulfates
  • Compounds useful for the present invention may also be administered in the form of hemisalts of acids and bases, for example, hemisulphate and hemicalcium salts.
  • Compounds useful for the present invention may also be administered in the form of complexes.
  • Complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts.
  • complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts.
  • the resulting complexes may be ionised, partially ionised, or non-ionised.
  • prodrug refers to a pharmacologically inactive derivative of a parent "drug” molecule that requires biotransformation (e.g., either spontaneous or enzymatic) within the target physiological system to release or convert the prodrug into the active drug.
  • Prodrugs are designed to overcome problems associated with stability, toxicity, lack of specificity, or limited bioavailability.
  • Exemplary prodrugs comprise an active drug molecule itself and a chemical masking group (e.g., a group that reversibly suppresses the activity of the drug).
  • Some preferred prodrugs are variations or derivatives of compounds that have groups cleavable under metabolic conditions.
  • prodrugs become pharmaceutically active in vivo or in vitro when they undergo solvolysis under physiological conditions or undergo enzymatic degradation or other biochemical transformation (e.g., phosphorylation, hydrogenation, dehydrogenation, glycosylation).
  • Prodrugs often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism. (See e.g., Bundgard, Design of Prodrugs, pp. 7-9, 21- 24, Elsevier, Amsterdam (1985); and Silverman, The Organic Chemistry of Drug Design and Drug Action, pp. 352-401 , Academic Press, San Diego, CA (1992)).
  • Common prodrugs include acid derivatives such as esters prepared by reaction of parent acids with a suitable alcohol (e.g., a lower alkanol), amides prepared by reaction of the parent acid compound with an amine, or basic groups reacted to form an acylated base derivative (e.g., a lower alkylamide).
  • a suitable alcohol e.g., a lower alkanol
  • amides prepared by reaction of the parent acid compound with an amine e.g., a lower alkylamide
  • Compounds useful for the present invention may also be administered as isotopically labelled derivatives of the BET-family bromodomain inhibitor wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds useful for the present invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 l and 125 l, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described.
  • BET-family bromodomain inhibitors for the pharmaceutical methods of the present invention, BET-family bromodomain inhibitors, and pharmaceutically acceptable salts thereof, will usually be administered in a pharmaceutically acceptable composition.
  • compositions suitable for use in the present invention can be in the form of sterile, non-pyrogenic liquid solutions or suspensions, coated capsules, suppositories, lyophilized powders, transdermal patches or other forms known in the art.
  • sterile injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • Formulations are provided herein comprising crystalline forms of the pharmaceutically active agent for slow absorption from subcutaneous or intramuscular injection. Additionally, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the compounds in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations may also be prepared by entrapping the drug in liposomes or microemulsions, which are compatible with body tissues.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, acetyl alcohol and
  • compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients ass lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Alternative formulations include those where the pharmaceutically active agent is in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, EtOAc, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the pharmaceutically active agent is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulations, ear drops, and the like are also contemplated.
  • compositions may also be formulated for delivery as a liquid aerosol or inhalable dry powder.
  • Liquid aerosol formulations may be nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles.
  • pharmaceutically acceptable carrier means a pharmaceutical ly-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the pharmaceutically active agent from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically-acceptable material such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the pharmaceutically active agent from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydrox
  • excipient refers to an inert substance added to a pharmacological composition to further facilitate administration of a pharmaceutically active agent.
  • excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • the compounds useful for the invention described herein may be administered to humans and other animals orally, parenterally, sublingually, by aerosolization or inhalation spray, rectally, intracisternally, intravaginally, intraperitoneally, bucally, intrathecally or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired.
  • parenteral as used herein includes subcutaneous injection, intravenous injection, intramuscular injection, intrasternal injection, or infusion techniques. Topical administration may also involve the use of transdermal administration such as transdermal patches or ionophoresis devices.
  • Effective amounts of the compounds useful for the invention generally include any amount sufficient to detectably modulate BET-family bromodomain activity, or to alleviate symptoms associated with diseases associated with BET-family bromodomain activity or susceptible to BET-family bromodomain activity modulation.
  • the specific dose of compound administered according to the methods of the invention to obtain therapeutic and/or prophylactic effect will vary depending upon the host treated and the particular mode of administration.
  • the specific dose level for any particular subject will depend upon a variety of factors including, for example, the specific compound administered, the route of administration, the condition being treated, and the individual being treated, including the age, body weight, general health, sex, diet, of the individual, the time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
  • the therapeutically effective amount for a given situation can be readily determined by routine experimentation and is within the skill and judgment of the ordinary clinician.
  • a typical daily dose (administered in single or divided doses) will contain a dosage level of from about 0.01 mg/kg to about 50-100 mg/kg of body weight of an active compound useful for the invention.
  • Preferred daily doses generally will be from about 0.05 mg/kg to about 20 mg/kg and ideally from about 0.1 mg/kg to about 10 mg/kg.
  • Factors such as clearance rate, half-life and maximum tolerated dose (MTD) can determine these using standard procedures.
  • MTD maximum tolerated dose
  • the dosing regimen may be adjusted to balance treatment efficacy whilst minimizing patient adverse events and thereby improving the safety profile. Such dosing adjustments would be made by taking into account routine parameters such as the half life of frataxin and drug exposure.
  • the present invention relates to any of the aforementioned embodiments, wherein the method comprises co-administering the BET-family bromodomain inhibitor, or pharmaceutically acceptable salt thereof, which a second pharmaceutically active ingredient, or pharmaceutically acceptable salt thereof.
  • co-administration refers to a combination of a compound of Formula (I) and one or more other pharmaceutically active ingredient, or a pharmaceutically acceptable salt thereof, includes the following:
  • the compounds useful for the present invention may be co-administered with one or more therapeutic agents selected from the group consisting of:
  • anti-hypertensive agents include: alpha adrenergic blockers; beta adrenergic blockers; calcium channel blockers (e.g., diltiazem, verapamil, nifedipine and amlodipine); vasodilators (e.g., hydralazine), diruetics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, torsemide, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone); renin inhibitors; ACE inhibitors (
  • Dual ET/AII antagonist e.g., compounds disclosed in WO 00/01389
  • neutral endopeptidase (NEP) inhibitors e.g., neutral endopeptidase (NEP) inhibitors
  • vasopepsidase inhibitors dual NEP-ACE inhibitors
  • gemopatrilat and nitrates e.g., gemopatrilat and nitrates.
  • An exemplary antianginal agent is ivabradine; a calcium channel blocker (L-type or T-type) including diltiazem, verapamil, nifedipine and amlodipine and mybefradil.
  • suitable cardiac glycosides include digitalis and ouabain;
  • Suitable diuretics include (a) loop diuretics such as furosemide (such as LASIXTM), torsemide (such as DEMADEXTM), bemetanide (such as BUMEXTM), and ethacrynic acid (such as EDECRINTM); (b) thiazide- type diuretics such as chlorothiazide (such as DIURILTM, ESIDRIXTM or HYDRODIURILTM), hydrochlorothiazide (such as MICROZIDETM or ORETICTM), benzthiazide, hydroflumethiazide (such as SALURONTM), bendroflumethiazide, methychlorthiazide, polythiazide, trichlormethiazide, and indapamide (such as LOZOLTM); (c) phthalimidine-type diuretics such as chlorthalidone (such as HYGROTONTM), and metolazone (such as HYGROTON
  • a compound useful for the present invention may be co-administered with a loop diuretic.
  • the loop diuretic is selected from furosemide and torsemide.
  • one or more compounds useful for the present invention may be co-administered with furosemide.
  • one or more compounds useful for the present invention may be co-administered with torsemide which may optionally be a controlled or modified release form of torsemide.
  • the diuretic can be a thiazide-type diuretic selected from the group consisting of chlorothiazide and hydrochlorothiazide.
  • one or more compounds useful for the invention may be co-administered with chlorothiazide. In still another embodiment, one or more compounds useful for the present invention may be co-administered with hydrochlorothiazide. In another embodiment, one or more compounds useful for the invention may be co-administered with a phthalimidine-type diuretic. In still another embodiment, the phthalimidine-type diuretic is chlorthalidone;
  • Suitable anti-diabetic agents include (e.g. insulins, metfomin, DPPIV inhibitors, GLP-1 agonists, analogues and mimetics, SGLT1 and SGLT2 inhibitors)
  • suitable anti-diabetic agents include an acetyl-CoA carboxylase- (ACC) inhibitor such as those described in WO2009144554, WO2003072197, WO2009144555 and WO2008065508, a diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitor, such as those described in WO09016462 or WO2010086820, AZD7687 or LCQ908, diacylglycerol O-acyltransferase 2 (DGAT-2) inhibitor, monoacylglycerol O-acyltransferase inhibitors, a PDE10 inhibitor, an AMPK activator, a
  • ACC acetyl-CoA carboxylase-
  • GSK1362885 a VPAC2 receptor agonist
  • SGLT2 inhibitors such as those described in E.C. Chao et al. Nature Reviews Drug Discovery 9, 551-559 (July 2010) including dapagliflozin, canagliflozin, empagliflozin, tofogliflozin (CSG452), ASP-1941 , THR1474, TS- 071 , ISIS388626 and LX421 1 as well as those in WO2010023594, a glucagon receptor modulator such as those described in Demong, D.E. et al.
  • GPR119 modulators particularly agonists, such as those described in WO2010140092, WO2010128425, WO2010128414, WO2010106457, Jones, R.M. et al. in Medicinal Chemistry 2009, 44, 149-170 (e.g. MBX-2982, GSK1292263, APD597 and PSN821), FGF21 derivatives or analogs such as those described in Kharitonenkov, A. et al.
  • TGR5 also termed GPBAR1 receptor modulators
  • GPBAR1 GPBAR1 receptor modulators
  • agonists such as those described in Zhong, M., Current Topics in Medicinal Chemistry, 2010, 10(4), 386-396 and INT777
  • GPR40 agonists such as those described in Medina, J.C., Annual Reports in Medicinal Chemistry, 2008, 43, 75- 85, including but not limited to TAK-875
  • GPR120 modulators particularly agonists, high affinity nicotinic acid receptor (HM74A) activators, and SGLT1 inhibitors, such as GSK1614235.
  • HM74A high affinity nicotinic acid receptor
  • anti-diabetic agents that can be combined with the compounds of the present invention can be found, for example, at page 28, line 35 through page 30, line 19 of WO2011005611.
  • Preferred anti-diabetic agents are metformin and DPP-IV inhibitors (e.g., sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin and saxagliptin).
  • antidiabetic agents could include inhibitors or modulators of carnitine palmitoyl transferase enzymes, inhibitors of fructose 1 ,6-diphosphatase, inhibitors of aldose reductase, mineralocorticoid receptor inhibitors, inhibitors of TORC2, inhibitors of CCR2 and/or CCR5, inhibitors of PKC isoforms (e.g.
  • PKCa ⁇ , PKCy
  • inhibitors of fatty acid synthetase inhibitors of serine palmitoyl transferase
  • modulators of GPR81 , GPR39, GPR43, GPR41 , GPR105, Kv1.3 retinol binding protein 4, glucocorticoid receptor, somatostain receptors (e.g. SSTR1 , SSTR2, SSTR3 and SSTR5), inhibitors or modulators of PDHK2 or PDHK4, inhibitors of MAP4K4, modulators of IL1 family including ILI beta, modulators of RXRalpha.
  • suitable anti-diabetic agents include mechanisms listed by Carpino, P. A., Goodwin, B. Expert Opin. Ther. Pat, 2010, 20(12), 1627-51 ;
  • anti-platelet agent Especially preferred anti-platelet agents are aspirin and clopidogrel.
  • anti-platelet agents denotes agents that inhibit platelet function, for example by inhibiting the aggregation, adhesion or granular secretion of platelets.
  • Agents include, but are not limited to, the various known non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, piroxicam, and pharmaceutically acceptable salts or prodrugs thereof.
  • NSAIDS non-steroidal anti-inflammatory drugs
  • NSAIDS aspirin (acetylsalicyclic acid or ASA) and COX-2 inhibitors such as celecoxib or piroxicam are preferred.
  • Suitable platelet inhibitory agents include llb/llla antagonists (e.g., tirofiban, eptifibatide, and abciximab), thromboxane-A2-receptor antagonists (e.g., ifetroban), thromboxane-A2-synthetase inhibitors, PDE3 inhibitors (e.g., Pletal, dipyridamole), and pharmaceutically acceptable salts or prodrugs thereof.
  • llb/llla antagonists e.g., tirofiban, eptifibatide, and abciximab
  • thromboxane-A2-receptor antagonists e.g., ifetroban
  • thromboxane-A2-synthetase inhibitors e.g., Pletal, dip
  • anti-platelet agents or platelet inhibitory agents
  • ADP adenosine diphosphate
  • Preferred P2Y12 receptor antagonists include ticagrelor, prasugrel, ticlopidine and clopidogrel, including pharmaceutically acceptable salts or prodrugs thereof.
  • Clopidogrel is an even more preferred agent. Ticlopidine and clopidogrel are also preferred compounds since they are known to be gentle on the gastro-intestinal tract in use;
  • an anti-thrombin agent including inhibitors of the serine protease thrombin.
  • various thrombin-mediated processes such as thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-1 and/or serotonin) and/or fibrin formation are disrupted.
  • thrombin inhibitors are known to one of skill in the art and these inhibitors are contemplated to be used in combination with the present compounds.
  • Such inhibitors include, but are not limited to, boroarginine derivatives, boropeptides, heparins, hirudin, argatroban, and melagatran, including pharmaceutically acceptable salts and prodrugs thereof.
  • Boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C- terminal alpha-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof.
  • hirudin includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin;
  • thrombolytics or fibrinolytic agents including agents that lyse blood clots (thrombi).
  • agents include tissue plasminogen activator (natural or recombinant) and modified forms thereof, anistreplase, urokinase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), factor Vila inhibitors, PAI-1 inhibitors (i.e., inactivators of tissue plasminogen activator inhibitors), alpha2-antiplasmin inhibitors, and anisoylated plasminogen streptokinase activator complex, including pharmaceutically acceptable salts or prodrugs thereof.
  • anistreplase refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in EP 028,489, the disclosure of which is hereby incorporated herein by reference herein.
  • urokinase as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase.
  • Suitable anti-arrythmic agents include: Class I agents (such as propafenone); Class II agents (such as metoprolol, atenolol, carvadiol and propranolol); Class III agents (such as sotalol, dofetilide, amiodarone, azimilide and ibutilide); Class IV agents (such as ditiazem and verapamil); K + channel openers such as ⁇ / c ⁇ inhibitors, and IK ui - inhibitors (e.g., compounds such as those disclosed in WO01/40231);
  • Class I agents such as propafenone
  • Class II agents such as metoprolol, atenolol, carvadiol and propranolol
  • Class III agents such as sotalol, dofetilide, amiodarone, azimilide and ibutilide
  • Class IV agents such as ditiazem and verapamil
  • K + channel openers
  • a factor Xa inhibitor including apixaban and rivaroxaban
  • an anti-coagulants for use in combination with the compounds of the present invention include heparins (e.g., unfractioned and low molecular weight heparins such as enoxaparin and dalteparin);
  • (x) other agents such as warfarin, unfractionated heparin, low molecular weight heparin, synthetic pentasaccharide, hirudin, argatrobanas, aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel, tirofiban, eptifibatide, abciximab, melagatran, disulfatohirudin, tissue plasminogen activator, modified tissue plasminogen activator, anistreplase, urokinase, and streptokinase;
  • neuroinflammatory and neurodegenerative agents include antidepressants, antipsychotics, anti-pain agents, anti-Alzheimer's agents, and anti-anxiety agents.
  • antidepressants include norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors
  • SSRIs monoamine oxidase inhibitors
  • MAOIs monoamine oxidase inhibitors
  • RIMAs reversible inhibitors of monoamine oxidase
  • SNRIs serotonin and noradrenaline reuptake inhibitors
  • CRF corticotropin releasing factor
  • Suitable norepinephrine reuptake inhibitors include tertiary amine tricyclics and secondary amine tricyclics.
  • Suitable tertiary amine tricyclics and secondary amine tricyclics include amitriptyline, clomipramine, doxepin, imipramine, trimipramine, dothiepin, butriptyline, nortriptyline, protriptyline, amoxapine, desipramine and maprotiline.
  • suitable SSRIs include fluoxetine, fluvoxamine, paroxetine, and sertraline.
  • monoamine oxidase inhibitors include isocarboxazid, phenelzine, and tranylcyclopramine.
  • suitable reversible inhibitors of monoamine oxidase include moclobemide.
  • SNRIs of use in the present invention include venlafaxine.
  • suitable atypical antidepressants include bupropion, lithium, trazodone and viloxazine.
  • anti-Alzheimer's agents include NMDA receptor antagonists such as memantine; and cholinesterase inhibitors such as donepezil and galantamine.
  • suitable classes of anti-anxiety agents that can be used in combination with the compounds useful for the present invention include benzodiazepines and serotonin 1A receptor (5-HT1A) agonists, and CRF antagonists.
  • Suitable benzodiazepines include alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, lorazepam, oxazepam, and prazepam.
  • Suitable 5- HT1A receptor agonists include buspirone and ipsapirone.
  • Suitable CRF antagonists include verucerfont.
  • Suitable atypical antipsychotics include paliperidone, ziprasidone, risperidone, aripiprazole, olanzapine, and quetiapine.
  • Suitable nicotine acetylcholine agonists include CP-601927 and varenicline.
  • Anti-pain agents include pregabalin, gabapentin, clonidine, neostigmine, baclofen, midazolam, ketamine and ziconotide;
  • an agent to reduce spasticity and spasms including, but not limited to, baclofen, tizanidine, benzodiazepines, dantrolene sodium, gabapentin and botulinum toxin;
  • an antioxidants including but not limited to, myeloperoxidase inhibitors (such as AZD-3241), NOX4 and other NOX enzymes (such as GKT-137831), vitamin E, Coenzyme Q, and N-acetyl cysteine;
  • NSAIDs non-steroidal anti-inflammatory drugs
  • COX1/2 inhibitors such as piroxicam, naproxen, flubiprofen, fenoprofen, ketoprofen, ibuprofen, etodolac (Lodine), mefanamic acid, sulindac, apazone, pyrazolones (such as phenylbutazone), salicylates (such as aspirin); selective COX2 inhibitors such as: celecoxib, rofecoxib, etoricoxib, valdecoxib, meloxicam;
  • an immunomodulatory and/ or anti-inflammatory agents including but not limited to, methotrexate, leflunomide, ciclesonide chloroquine, hydroxychloroquine, d- penicillamine, auranofin, sulfasalazine, sodium aurothiomalate, cyclosporine, azathioprine, cromolyn, hydroxycarbamide, retinoids, fumarates (such as monomethyl and dimethyl fumarate), glatiramer acetate, mitoxantrone, teriflunomide, suplatast tosilate, mycophenolate mofetil and cyclophosphamide, laquinimod, voclosporin, PUR-118, AMG 357, AMG 81 1 , BCT197;
  • Nrf2 pathway activators including but not limited to, fumarates, sulfurophane and bardoxolone methyl
  • an interferon including, but not limited to, interferon beta-1 a and interferon beta- l b.
  • the additional therapeutic agent is an agent useful for treating Friedreich's ataxia; treating a condition or a disease associated with decreased expression of frataxin or a decreased level of frataxin; regulating the expression of frataxin in a cell; and / or for increasing the expression of frataxin in a cell.
  • Such agents include, but are not limited to, those selected from the group consisting of carbanylated erythropoietin; interferon gammal b; methylprednisolone; idebenone; quinone antioxidants such as A00001 - alpha tocopherolquinone and EP1-743; iron chlating agents cuah as deferiprone; Nrf2 enhancers such as RTA-408; acetyl- 1 -carnitine; pioglitazone; di-deutero synthetic analogues of linoleic acid ethyl ester such as RT001 ; ginkgo biloba extract such as EGb761 ; free radical scavengers such as indole-3- propionic acid or EP20629; nicotinamide; and riluzole.
  • compositions may conveniently be combined in the form of a kit suitable for co-administration of the compositions.
  • Test compounds JQ-1(+), JQ-1 (-), and l-BET-762 were obtained from Selleck Chemicals, Houston, Texas, USA. Other test compounds were obtained from Pfizer's library, which compounds had been prepared in accordance with methods from the art.
  • RVX-208 was prepared in accordance with the method set out in WO2008/092231 ;
  • l-BET-151 was prepared in accordance with the method set out in WO2011054843;
  • N-(2-hydroxy-3-methylquinolin-6-yl)piperidine-1-sulfonamide was prepared in accordance with the method set out in WO2013/027168;
  • N-[4-(2,4- difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1 H-pyrrolo[2,3-c]pyridin- 4- yl)phenyl]ethanesulfonamide was prepared in accordance with the method set out in WO 2013/097052 or WO
  • BET-family bromodomain inhibitors useful for the present invention may be measured in the BRD4 Fluorescence polarization (FP) competition binding assay where the compounds can be screened for their activity at BRD4 BD1 , BRD4 BD2 or both BRD4 BD1 and BD2.
  • FP Fluorescence polarization
  • His-tagged BRD4 BD1 44-160
  • PFI-411 FP Cy5-labeled FP probe
  • His-tagged BRD4 BD2 was purchased from BPS Bioscience.
  • the final assay concentration (FAC) of PFI-41 1 FP was 2 nM, the FAC of BRD4 BD1 and BRD4 BD2 was 50 nM, the FAC of test compound ranged from 120 to 0.0012 ⁇ and the FAC of DMSO was 0.4%.
  • polarization values were measured with an Envision 2103 multilabel reader (Perkin Elmer) using a Cy5 dual enhanced mirror and excitation at 620 nm and emission at 688 nm. The percent (%) effect was calculated for each concentration of test compound and was relative to the amount of polarization signal produced by the positive and negative control wells contained within each assay plate.
  • the concentrations and % effect values for test compounds were plotted versus each other with a proprietary curve fitting program using a four-parameter logistic dose response equation and the concentration of compound required for 50% effect (IC50) was determined.
  • the Ki values of competitive inhibitors are calculated using the equation described by Nikolovska-Coleska et al. (Development and optimization of a binding assay for the XIAP BIR3 domain using fluorescence polarization. Analytical Biochemistry (2004) 332: 261-273, incorporated by reference herein).
  • Example 2 Frataxin levels in Friedreich's Ataxia patient derived lymphoblasts are increased on treatment of with JQ-1 (+) and l-BET-762
  • Friedreich's Ataxia lymphoblasts GM 15850 (FXN alleles carrying ⁇ 650 and 1030 GAA repeats) were obtained from NIGMS Human Genetic Cell Repository at the Coriell Institute for Medical Research and cultured in complete medium containing RPMI1640 media supplemented with 10% Fetal bovine serum (Invitrogen) and 20mM Hepes buffer (Invitrogen). Prior to treatment with a test compound, 500,000 cells were seeded in 900ul complete medium were seeded per well in a 12 well plate, and subsequently treated with the test compound (10mM in DMSO) which had been diluted in 100ul optimem (Invitrogen) to achieve a final concentration of test compound of 5.0 ⁇ ; 0.5 ⁇ or 0.05 ⁇ .
  • Cells were incubated in a 37°C incubator (5% C0 2 ) for 72h before harvesting.
  • cells were collected by centrifugation at 500xg for 5 mins, then washed once in 1 ml phosphate buffered saline (PBS) before lysis in NP40 lysis buffer (0.5%NP40+50mM Tris pH7.5, 150mM NaCI supplemented with protease and phosphatase inhibitors from Roche) for 30 mins on ice . Lysates were finally cleared by centrifugation at max speed in a refrigerated microcentrigue for 10 mins.
  • PBS phosphate buffered saline
  • Protein concentration was determined using the Protein 660 reagent (Pierce) (results shown in Figure 2, total protein concentration in mg/ml) and lysates were prepared for polyacrylamide gel electrophoresis (PAGE) analysis by dilution in lysis buffer supplemented with LDS sample buffer (Invitrogen) containing 10% dithiothreitol. Samples (5-10ug/lane) were then denatured by heating at 100C for 5 mins, loaded on a 4-12% BisTris Nupage gel (Invitrogen) and resolved in MES running buffer (Invitrogen) supplemented with Nupage antioxidant (Invitrogen). Proteins were transferred to a nitrocellulose membrane (0.2um from Biorad) using the Trans-Blot Turbo (Biorad).
  • Membrane was blocked in 5% milk in Tris buffered saline supplemented with 0.05% Tween 20 (TBST) for 1 h and left in primary antibody anti-FXN (ab110328 from Abeam; 1 : 1000 dilution) diluted in blocking buffer overnight at 4C. Membrane was then washed three times in TBST and incubated in blocking buffer containing secondary anti-mouse antibody conjugated to HRP (1 :7500 anti-mouse IgG HRP) for 30 mins and then subjected to four washes in TBST. Similarly, anti ⁇ -actin (Cell Signaling; 1 :12000 dilution) western blotting was used as lane loading control.
  • HRP 1 :7500 anti-mouse IgG HRP
  • GM 15850 cells (Coriell) were subjected to a dose-response treatment with JQ-
  • Example 4 The cytotoxic effect of JQ-1(+) on healthy AG14725 lymphoblasts and Friedreich's Ataxia GM 15850 lymphoblasts was measured
  • the lymphoblasts were seeded in a 96 well plate, (40,000 cells per well in 180 ⁇ _ of RPMI1640 media supplemented with 10% Fetal bovine serum (Invitrogen) and 20mM Hepes buffer (Invitrogen)) and were incubated in a 37°C incubator (5% CO 2 ) for 72h before harvesting with varying concentrations of the test compound (duplicate treatment per condition).
  • the test compound was prepared by dilution of a 10mM stock solution in DMSO with optimen (Invitrogen) to the desired test concentration.
  • cell viability was determined using the CellTiter Glo luminescent assay (Promega) according to the protocol provided by the manufacturer. The results are shown in Figure 5.
  • Example 5 Frataxin levels in Friedreich's Ataxia patient derived lymphoblasts are increased on treatment of with a variety of different BET-family bromodomain inhibitor scaffolds.
  • GM 15850 lymphoblasts were prepared according to the directions provided in Example 2 above and treated with a 1 ⁇ solution of the test compound for 72 hours, as described previously.
  • the test compound was prepared by dilution of a 10mM stock solution in DMSO with optimen (Invitrogen) to the desired test concentration.
  • the compounds tested were:
  • the levels of intermediate and mature frataxin in the cells were assessed by Western Blotting using the same protocol as described in Example 2 above. Lysates were also subjected to Western Blotting again using the same protocol with an antibody raised against mitochondrial aconitase (mAco2); the antibody was obtained from Abeam (ab129105).
  • the results demonstrate that the level of both intermediate and mature frataxin was increased for all compounds tested, although the increase seen with Cmpdl was reduced when compared to the other compounds tested which, without wishing to be bound by theory, may possibly be a result of the reduced solubility of Cmpdl in the test medium.
  • GM03665 cells (Coriell; -700 and 400 GAA repeats) were seeded at 100,000 cells/well in a 6-well plate in 2ml_ of DMEM media (Invitrogen) supplemented with 10% Fetal bovine serum (Invitrogen) and 20mM Hepes buffer (Invitrogen)). The cells were reverse transfected using transfection reagent Dharmafect I (Dharmacon) following manufacturer's recommendation mixed with the following siRNA duplex at a concentration of 25nM in optimen (Invitrogen).
  • GM03665 cells (Coriell; -700 and 400 GAA repeats) were seeded at 100,000 cells/well in a 6-well plate in 2ml_ of DMEM media (Invitrogen) supplemented with 10% Fetal bovine serum (Invitrogen) and 20mM Hepes buffer (Invitrogen)). The cells were reverse transfected using transfection reagent Dharmafect I (Dharmacon) following manufacturer's recommendation mixed with the following siRNA duplex at a concentration of 25nM in optimen (Invitrogen).

Abstract

La présente invention concerne un procédé de traitement d'une affection ou d'une maladie associée à des teneurs réduites ou à une activité réduite de frataxine, notamment l'ataxie de Friedreich, comprenant l'administration à un sujet le nécessitant d'une quantité thérapeutiquement efficace d'un inhibiteur de bromodomaine de la famille BET, ou un sel pharmaceutiquement acceptable de celui-ci. L'invention concerne des procédés, des utilisations pharmaceutiques et des compositions pharmaceutiques associés.
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WO2019029554A1 (fr) * 2017-08-10 2019-02-14 浙江海正药业股份有限公司 Dérivé sulfonamide, sa méthode de préparation et son application en médecine
WO2019195467A1 (fr) * 2018-04-04 2019-10-10 Retrotope, Inc. Composition isotopiquement modifiée et ses utilisations thérapeutiques
US10517877B2 (en) 2016-03-30 2019-12-31 Wisconsin Alumni Research Foundation Compounds and methods for modulating frataxin expression
US10532054B2 (en) 2007-02-01 2020-01-14 Resverlogix Corp. Compounds for the prevention and treatment of cardiovascular diseases
WO2020086551A1 (fr) * 2018-10-23 2020-04-30 Wisconsin Alumni Research Foundation Nouvelle génération de facteurs de transcription synthétiques
CN113881683A (zh) * 2021-10-14 2022-01-04 山西大学 一种飞蝗zen基因dsRNA及其应用
US11759533B2 (en) 2017-03-29 2023-09-19 Wisconsin Alumni Research Foundation Methods and compositions for modulating gene expression

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US10131640B2 (en) 2009-03-18 2018-11-20 Resverlogix Corp. Anti-inflammatory agents
US11407719B2 (en) 2009-03-18 2022-08-09 Resverlogix Corp. Anti-inflammatory agents
US10517877B2 (en) 2016-03-30 2019-12-31 Wisconsin Alumni Research Foundation Compounds and methods for modulating frataxin expression
US11759533B2 (en) 2017-03-29 2023-09-19 Wisconsin Alumni Research Foundation Methods and compositions for modulating gene expression
WO2019029554A1 (fr) * 2017-08-10 2019-02-14 浙江海正药业股份有限公司 Dérivé sulfonamide, sa méthode de préparation et son application en médecine
CN109384784A (zh) * 2017-08-10 2019-02-26 浙江海正药业股份有限公司 磺酰胺类衍生物、其制备方法及其在医药上的用途
CN109384784B (zh) * 2017-08-10 2021-01-12 浙江海正药业股份有限公司 磺酰胺类衍生物、其制备方法及其在医药上的用途
WO2019195467A1 (fr) * 2018-04-04 2019-10-10 Retrotope, Inc. Composition isotopiquement modifiée et ses utilisations thérapeutiques
WO2020086551A1 (fr) * 2018-10-23 2020-04-30 Wisconsin Alumni Research Foundation Nouvelle génération de facteurs de transcription synthétiques
CN113881683A (zh) * 2021-10-14 2022-01-04 山西大学 一种飞蝗zen基因dsRNA及其应用
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