US20040087657A1 - Treatment of neurodegenerative diseases and cancer of the brain using histone deacetylase inhibitors - Google Patents

Treatment of neurodegenerative diseases and cancer of the brain using histone deacetylase inhibitors Download PDF

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US20040087657A1
US20040087657A1 US10/273,401 US27340102A US2004087657A1 US 20040087657 A1 US20040087657 A1 US 20040087657A1 US 27340102 A US27340102 A US 27340102A US 2004087657 A1 US2004087657 A1 US 2004087657A1
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disease
histone deacetylase
diseases
brain
treatment
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Victoria Richon
Paul Marks
Richard Rifkind
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Memorial Sloan Kettering Cancer Center
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Assigned to SLOAN-KETTING INSTITUTE FOR CANCER RESEARCH reassignment SLOAN-KETTING INSTITUTE FOR CANCER RESEARCH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MARKS, PAUL A., RIFKIND, RICHARD A, RICHON, VICTORIA A.
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Priority to US11/282,420 priority patent/US7879865B2/en
Priority to US13/017,447 priority patent/US20110124731A1/en
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • 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
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    • 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
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • HDACs histone deacetylase
  • HDAC inhibitors fall into four general classes: 1) short-chain fatty acids (e.g., 4-phenylbutyrate and valproic acid); hydroxamic acids (e.g., SAHA, Pyroxamide, trichostatin A (TSA), oxamflatin and CHAPs, such as, CHAP1 and CHAP 31); 3) cyclic tetrapeptides (Trapoxin A and Apicidin); 4) benzamides (e.g., MS-275); and other compounds such as Scriptaid. Examples of such compounds can be found in U.S. Pat. No. 5,369,108, issued on Nov. 29, 1994, U.S. Pat. No. 5,700,811, issued on Dec. 23, 1997, and U.S. Pat.
  • Preferred hydroxamic acid based HDAC inhibitors are suberoylanilide hydroxamic acid (SAHA) and pyroxamide.
  • SAHA has been shown to bind directly in the catalytic pocket of the histone deacetylase enzyme.
  • SAHA induces cell cycle arrest, differentiation and/or apoptosis of transformed cells in culture and inhibits tumor growth in rodents.
  • SAHA is effective at inducing these effects in both solid tumors and hematological cancers. It has been shown that SAHA is effective at inhibiting tumor growth in animals with no toxicity to the animal.
  • the SAHA-induced inhibition of tumor growth is associated with an accumulation of acetylated histones in the tumor.
  • SAHA is effective at inhibiting the development and continued growth of carcinogen-induced (N-methylnitrosourea) mammary tumors in rats.
  • SAHA was administered to the rats in their diet over the 130 days of the study.
  • SAHA is a nontoxic, orally active antitumor agent whose mechanism of action involves the inhibition of histone deacetylase activity.
  • HDAC inhibitors for example, SAHA and pyroxamide can cross the blood brain barrier at sufficient amounts to significantly inhibit HDAC activity causing the accumulation of acetylated histones in the brain. This discovery therefore provides for the use of HDAC inhibitors in the treatment of disorders of the central nervous system including cancer of the brain and neurodegenerative diseases.
  • the present application is directed to a method of treating diseases of the central nervous system (CNS) comprising administering to a individual in need of treatment a therapeutically effective amount of an inhibitor of histone deacetylase.
  • the CNS disease is a neurodegenerative disease.
  • the neurogenerative disease is an inherited neurodegenerative disease, such as those inherited neurodegenerative diseases which are polyglutamine expansion diseases.
  • the individual can be a mammal such as a primate or human.
  • FIG. 1 is a scan of a Western blot and Coomassie stained gel indicating levels of acetylated histone ( ⁇ AcH3) at the indicated timepoints following treatment with vehicle (DMSO) or three doses of SAHA (100 mg/kg/hr).
  • FIG. 2 is a scan of a Western blot and Coomassie stained gel indicating levels of acetylated histone ( ⁇ AcH4) at the indicated timepoints following treatment with vehicle (DMSO) or three doses of Pyroxamide (100 mg/kg/hr).
  • the present application is directed to a method of treating diseases of the central nervous system (CNS) comprising administering to a individual in need of treatment a therapeutically effective amount of an inhibitor of histone deacetylase.
  • the CNS disease is a neurodegenerative disease.
  • the neurogenerative disease is an inherited neurodegenerative disease, such as those inherited neurodegenerative diseases which are polyglutamine expansion diseases.
  • the neurodegenerative disease is Huntington's disease.
  • the individual can be a mammal such as a primate or human.
  • Therapeutically effective amount refers to an amount which elicits the desired therapeutic effect.
  • the therapeutic effect is dependent upon the disease being treated. As such, the therapeutic effect can be a decrease in the severity of symptoms associated with the disease and/or inhibition (partial or complete) of progression of the disease.
  • the amount needed to elicit the therapeutic response can be determined based on the age, health, size and sex of the patient. Optimal amounts can also be determined based on monitoring of the patient's response to treatment.
  • neurodegenerative diseases of the central nervous system
  • diseases of the central nervous system are referred to as neurodegenerative, indicating that they are characterized by gradually evolving, relentlessly progressive neuronal death occurring for reasons that are still largely unknown.
  • the identification of these diseases depends upon exclusion of such possible causative factors as infections, metabolic derangements, and intoxications.
  • a considerable proportion of the disorders classed as neurogenerative are genetic, with either dominant or recessive inheritance. Others, however, occur only sporadically as isolated instances in a given family.
  • Classification of the degenerative diseases cannot be based upon any exact knowledge of cause or pathogenesis; their subdivision into individual syndromes rests on descriptive criteria based largely upon neuropathologic and clinical aspects. This group of diseases presents as several distinct clinical syndromes, the recognition of which can assist the clinician in arriving at a diagnosis.
  • polyglutamine polyglutamine
  • polyQ polyglutamine
  • the underlying mutation is an expansion of a CAG trinucleotide repeat that encodes polyQ in the respective disease protein. All are progressive, ultimately fatal disorders that typically begin in adulthood and progress over 10 to 30 years.
  • the clinical features and pattern of neuronal degeneration differ among the diseases, yet increasing evidence suggests that polyQ diseases share important pathogenic features.
  • abnormal protein conformations(s) promoted by polyQ expansion seem to be central to pathogenesis.
  • This class of PolyQ expansion neurodegenerative disease are Huntington's Disease (HD), Dentatorubralpallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA), and five spinocerebellar ataxias (SCA1, SCA2, SCA3/MJD(Machado-Joseph Disease), SCA6 and SCA7). These diseases are listed in the general listing of neurodegenrative disease below. Many of these diseases not yet connected with PolyQ expansion are thought to result from abnormal protein folding and aggregation (e.g., Alzheimer's disease).
  • neurodegenerative diseases can be grouped as follows:
  • Torsion dystonia torsion spasm; dystonia musculorum deformans
  • HDAC inhibitors suitable for use in the invention include, but are not limited to the following specific structures:
  • HDAC inhibitors which can be useful can include the four general classes described above: 1) short-chain fatty acids (e.g., 4-phenylbutyrate and valproic acid); hydroxamic acids (e.g., SAHA, Pyroxamide, trichostatin A (TSA), oxamflatin and CHAPs, such as, CHAP1 and CHAP 31); 3) cyclic tetrapeptides (Trapoxin A and Apicidin; 4) benzamides (e.g., MS-275); and other compounds such as Scriptaid. Examples of such compounds can be found in U.S. Pat. No. 5,369,108, issued on Nov. 29, 1994, U.S. Pat. No.
  • mice (2 mice per condition) were injected by intraperitoneal injection (IP) with either SAHA (100 mg/kg), pyroxamide (200 mg/kg), or vehicle (dimethylsulfoxide). Each mouse was administered three injections at the indicated dose at 1 hour intervals. After the final IP injection tissues (brain, spleen or liver) were isolated at the times indicated. Histones were isolated from tissues essentially as described by Yoshida et al., (1990) J. Biol. Chem. 265:17174-17179. Equal amounts of histones (1 ⁇ g) were electrophoresed on 15% SDS-polyacrylamide gels and transferred to Hybond-P filters (Amersham).
  • IP intraperitoneal injection

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US11/282,420 US7879865B2 (en) 2001-10-16 2005-11-18 Treatment of cancer of the brain using histone deacetylase inhibitors
US13/017,447 US20110124731A1 (en) 2001-10-16 2011-01-31 Treatment Of Neurodegenerative Diseases And Cancer Of The Brain Using Histone Deacetylase Inhibitors

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