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Publication numberUS20040087657 A1
Publication typeApplication
Application numberUS 10/273,401
Publication dateMay 6, 2004
Filing dateOct 16, 2002
Priority dateOct 16, 2001
Also published asCA2463552A1, CA2463552C, EP1443928A2, EP1443928A4, EP1443928B1, EP2269609A2, EP2269609A3, US7879865, US20060079551, US20110124731, WO2003032921A2, WO2003032921A3
Publication number10273401, 273401, US 2004/0087657 A1, US 2004/087657 A1, US 20040087657 A1, US 20040087657A1, US 2004087657 A1, US 2004087657A1, US-A1-20040087657, US-A1-2004087657, US2004/0087657A1, US2004/087657A1, US20040087657 A1, US20040087657A1, US2004087657 A1, US2004087657A1
InventorsVictoria Richon, Paul Marks, Richard Rifkind
Original AssigneeRichon Victoria M., Marks Paul A., Rifkind Richard A.
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Treatment of neurodegenerative diseases and cancer of the brain using histone deacetylase inhibitors
US 20040087657 A1
Abstract
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. In particular embodiments, the CNS disease is a neurodegenerative disease. In further embodiments, 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.
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Claims(12)
What is claimed is:
1. A method of inhibiting histone deacetylase in the brain of a mammal comprising administering to the mammal a histone deacetylase inhibiting amount of a histone deacetylase inhibitor compound.
2. The method of claim 1, wherein the histone deacetylase inhibitor compound is selected from:
or a pharmaceutically acceptable salt thereof.
3. The method of claim 2, wherein the histone deacetylase inhibitor compound is selected from:
or a pharmaceutically acceptable salt thereof.
4. A method of treating a disease of the central nervous system in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a histone deacetylase inhibitor compound.
5. The method of claim 4, wherein the disease is a polyglutamine expansion disease.
6. The method of claim 5, wherein the polyglutamine expansion disease is Huntington's disease.
7. The method of claim 4, wherein the individual is a human.
8. The method of claim 4, wherein the inhibitor of histone deacetylase is selected from:
or a pharmaceutically acceptable salt thereof.
9. The method of claim 8, wherein the histone deacetylase inhibitor compound is selected from:
or a pharmaceutically acceptable salt thereof.
10. A method of treating a brain cancer in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of a histone deacetylase inhibitor compound.
11. The method of claim 10, wherein the histone deacetylase inhibitor is selected from:
or a pharmaceutically acceptable salt thereof.
12. The method of claim 11, wherein the histone deacetylase inhibitor is selected from:
or a pharmaceutically acceptable salt thereof.
Description
    RELATED APPLICATIONS
  • [0001]
    This application claims the benefit of U.S. Provisional Application No. 60/329,705 filed on Oct. 16, 2001. The entire teachings of the above-referenced application are incorporated herein by reference.
  • BACKGROUND OF THE INVENTION
  • [0002]
    Compounds which inhibit histone deacetylase (HDACs) have been shown to cause growth arrest, differentiation and/or apoptosis of many different types of tumor cell in vitro and in vivo. HDACs catalyze the removal of the acetyl group from the lysine residues in the N-terminal tails of nucleosomal core histones resulting in a more compact chromatin structure, a configuration that is generally associated with repression of transcription. These 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. No. 5,773,474, issued on Jun. 30, 1998 to Breslow et al., U.S. Pat. No. 5,055,608, issued on Oct. 8, 1991, and U.S. Pat. No. 5,175,191, issued on Dec. 29, 1992 to Marks et al., as well as, Yoshida, M., et al., Bioassays 17, 423-430 (1995), Saito, A., et al., PNAS USA 96, 4592-4597, (1999), Furamai R. et al., PNAS USA 98 (1), 87-92 (2001), Komatsu, Y., et al., Cancer Res. 61(11), 4459-4466 (2001), Su, G. H., et al., Cancer Res. 60, 3137-3142 (2000), Lee, B. I. et al., Cancer Res. 61(3), 931-934, Suzuki, T., et al., J. Med. Chem. 42(15), 3001-3003 (1999) and published PCT Application WO 01/18171 published on Mar. 15, 2001 to Solan-Kettering Institute for Cancer Research and The Trustees of Columbia University the entire content of all of which are hereby incorporated by reference.
  • [0003]
    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. Thus, SAHA is a nontoxic, orally active antitumor agent whose mechanism of action involves the inhibition of histone deacetylase activity.
  • SUMMARY OF THE INVENTION
  • [0004]
    It has been surprisingly discovered that certain 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.
  • [0005]
    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. In particular embodiments, the CNS disease is a neurodegenerative disease. In further embodiments, the neurogenerative disease is an inherited neurodegenerative disease, such as those inherited neurodegenerative diseases which are polyglutamine expansion diseases.
  • [0006]
    The individual can be a mammal such as a primate or human.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • [0007]
    [0007]FIG. 1 is a scan of a Western blot and Coomassie stained gel indicating levels of acetylated histone (αAcH3) at the indicated timepoints following treatment with vehicle (DMSO) or three doses of SAHA (100 mg/kg/hr).
  • [0008]
    [0008]FIG. 2 is a scan of a Western blot and Coomassie stained gel indicating levels of acetylated histone (αAcH4) at the indicated timepoints following treatment with vehicle (DMSO) or three doses of Pyroxamide (100 mg/kg/hr).
  • DETAILED DESCRIPTION OF THE INVENTION
  • [0009]
    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. In particular embodiments, the CNS disease is a neurodegenerative disease. In further embodiments, the neurogenerative disease is an inherited neurodegenerative disease, such as those inherited neurodegenerative diseases which are polyglutamine expansion diseases. In a preferred embodiment, the neurodegenerative disease is Huntington's disease.
  • [0010]
    The individual can be a mammal such as a primate or human.
  • [0011]
    Therapeutically effective amount as that term is used herein 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.
  • [0012]
    Generally, 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.
  • [0013]
    However, research in the past decade has uncovered a new classification of inherited neurodegenerative diseases, the polyglutamine (polyQ) expansion diseases. In each, 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. In particular, 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).
  • [0014]
    Generally, neurodegenerative diseases can be grouped as follows:
  • [0015]
    I. Disorders characterized by progressive dementia in the absence of other prominent neurologic signs.
  • [0016]
    A. Alzheimer's disease
  • [0017]
    B. Senile dementia of the Alzheimer type
  • [0018]
    C. Pick's disease (lobar atrophy)
  • [0019]
    II. Syndromes combining progressive dementia with other prominent neurologic abnormalities
  • [0020]
    A. Mainly in adults
  • [0021]
    1. Huntington's disease
  • [0022]
    2. Multiple system atrophy combining dementia with ataxia and/or manifestations of Parkinson's disease
  • [0023]
    3. Progressive supranuclear aplsy (Steel-Richardson-Olszewski)
  • [0024]
    4. Diffuse Lewy body disease
  • [0025]
    5. Corticodentatonigral degeneration
  • [0026]
    B. Mainly in children or young adults
  • [0027]
    1. Hallervorden-Spatz disease
  • [0028]
    2. Progressive familial myoclonic epilepsy
  • [0029]
    III. Syndromes of gradually developing abnormalities of posture and movement
  • [0030]
    A. Paralysis agitans (Parkinson's disease)
  • [0031]
    B. Striatonigral degeneration
  • [0032]
    C. Progressive supranuclear palsy
  • [0033]
    D. Torsion dystonia (torsion spasm; dystonia musculorum deformans)
  • [0034]
    E. Spasmodic torticollis and other dyskinesis
  • [0035]
    F. Familial tremor
  • [0036]
    G. Gilles de la Tourette syndrome
  • [0037]
    IV. Syndromes of progressive ataxia
  • [0038]
    A. Cerebellar degenerations
  • [0039]
    1. Cerebellar cortical degeneration
  • [0040]
    2. Olivopontocerebellar atrophy (OPCA)
  • [0041]
    B. Spinocerebellar degeneration (Friedreich's atazia and related disorders)
  • [0042]
    V. Syndrome of central autonomic nervous system failure (Shy-Drager syndrome)
  • [0043]
    VI. Syndromes of muscular weakness and wasting without sensory changes (motor neuron disease
  • [0044]
    A. Amyotrophic lateral sclerosis
  • [0045]
    B. Spinal muscular atrophy
  • [0046]
    1. Infantile spinal muscular atrophy (Werdnig-Hoffman)
  • [0047]
    2. Juvenile spinal muscular atrophy (Wohlfart-Kugelberg-Welander)
  • [0048]
    3. Other forms of familial spinal muscular atrophy
  • [0049]
    C. Primary lateral sclerosis
  • [0050]
    D. Hereditary spastic paraplegia
  • [0051]
    VII. Syndromes combining muscular weakness and wasting with sensory changes (progressive neural muscular atrophy; chronic familial polyneuropathies)
  • [0052]
    A. Peroneal muscular atrophy (Charcot-Marie-Tooth)
  • [0053]
    B. Hypertrophic interstitial polyneuropathy (Dejerine-Sottas)
  • [0054]
    C. Miscellaneous forms of chronic progressive neuropathy
  • [0055]
    VIII. Syndromes of progressive visual loss
  • [0056]
    A. Pigmentary degeneration of the retina (retinitis pigmentosa)
  • [0057]
    B. Hereditary optic atrophy (Leber's disease)
  • [0058]
    HDAC inhibitors suitable for use in the invention include, but are not limited to the following specific structures:
  • [0059]
    Further, 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. 5,700,811, issued on Dec. 23, 1997, and U.S. Pat. No. 5,773,474, issued on Jun. 30, 1998 to Breslow et al., U.S. Pat. No. 5,055,608, issued on Oct. 8, 1991, and U.S. Pat. No. 5,175,191, issued on Dec. 29, 1992 to Marks et al., as well as, Yoshida, M., et al., Bioassays 17, 423-430 (1995), Saito, A., et al., PNAS USA 96, 4592-4597, (1999), Furamai R. et al., PNAS USA 98 (1), 87-92 (2001), Komatsu, Y., et al., Cancer Res. 61(11), 4459-4466 (2001), Su, G. H., et al., Cancer Res. 60, 3137-3142 (2000), Lee, B. I. et al., Cancer Res. 61(3), 931-934, Suzuki, T., et al., J. Med. Chem. 42(15), 3001-3003 (1999) and published PCT Application WO 01/18171 published on Mar. 15, 2001 to Sloan-Kettering Institute for Cancer Research and The Trustees of Columbia University the entire content of all of which are hereby incorporated by reference.
  • EXPERIMENTAL METHODS
  • [0060]
    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 μg) were electrophoresed on 15% SDS-polyacrylamide gels and transferred to Hybond-P filters (Amersham). Filters were blocked with 3% milk and probed with a rabbit purified polyclonal anti-acetylated histone H4 antibody (αAc-H4) and anti-acetylated histone H3 antibody (αAc-H3) (Upstate Biotechnology, Inc.). Levels of acetylated histone were visualized using a horseradish peroxidase-conjugated goat anti-rabbit antibody (1:5000) and the SuperSignal chemiluminescent substrate (Pierce). As a loading control for the histone proteins, parallel gels were run and stained with Coomassie Blue (CB). The results are shown in FIGS. 1 and 2.
Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US5330744 *Nov 14, 1988Jul 19, 1994Sloan-Kettering Institute For Cancer ResearchMethod for increasing sensitivity to chemically induced terminal differentiation
US5608108 *Apr 17, 1995Mar 4, 1997Sloan-Kettering Institute For Cancer ResearchPotent inducers of terminal differentiation and method of use thereof
US5668179 *Jun 7, 1995Sep 16, 1997The Trustees Of Columbia University In The City Of New YorkPotent inducers of terminal differentiation and method of use thereof
US5840960 *Jun 7, 1995Nov 24, 1998Sloan-Kettering Institute For Cancer ResearchPotent inducers of terminal differentiation and method of use thereof
US5932616 *Apr 4, 1994Aug 3, 1999Sloan-Kettering Institute For Cancer ResearchPotent inducers of terminal differentiation and methods of use thereof
US6087367 *May 18, 1999Jul 11, 2000Sloan-Kettering Institute For Cancer ResearchPotent inducers of terminal differentiation and methods of use thereof
US6495719 *Mar 27, 2001Dec 17, 2002Circagen PharmaceuticalHistone deacetylase inhibitors
US6511990 *Aug 24, 2000Jan 28, 2003Sloan-Kettering Institute For Cancer ResearchClass of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof
US6656905 *Oct 8, 1999Dec 2, 2003Fujisawa Pharmaceutical Co., Ltd.Cyclic tetrapeptide compound and use thereof
US20020061860 *Aug 6, 2001May 23, 2002Zuomei LiAntisense oligonucleotide inhibition of specific histone deacetylase isoforms
US20020065282 *Dec 4, 2001May 30, 2002Guy GeorgesTetralone derivatives
US20020103192 *Mar 14, 2001Aug 1, 2002Curtin Michael L.Inhibitors of histone deacetylase
US20020142859 *Feb 22, 2002Oct 3, 2002Callaway Golf CompanyMultiple material golf club head
US20040077591 *Mar 27, 2003Apr 22, 2004The Brigham And Women's Hospital, Inc.Histone deacetylase inhibitors for the treatment of multiple sclerosis, amyotrophic lateral sclerosis and Alzheimer's Disease
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US7126001 *Oct 25, 2002Oct 24, 2006Sloan-Kettering Institute For Cancer ResearchClass of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof
US7199134Apr 1, 2004Apr 3, 2007Sloan-Kettering Institute For Cancer ResearchHydroxamic acid compounds and methods of use thereof
US7345174Jun 22, 2006Mar 18, 2008Sloan-Kettering Institute For Cancer ResearchCytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof
US7732475Jul 13, 2006Jun 8, 2010Takeda San Diego, Inc.Histone deacetylase inhibitors
US7741494Oct 31, 2007Jun 22, 2010Takeda San Diego, Inc.Histone deacetylase inhibitors
US7772245Feb 14, 2006Aug 10, 2010Miikana Therapeutics, Inc.Inhibitors of histone deacetylase
US7799803Feb 22, 2007Sep 21, 2010The Trustees Of Columbia University In The City Of New YorkHydroxamic acid compounds and methods of use thereof
US7879865Nov 18, 2005Feb 1, 2011Sloan-Kettering Institute For Cancer ResearchTreatment of cancer of the brain using histone deacetylase inhibitors
US7935724Oct 8, 2004May 3, 2011Merck Hdac Research, LlcThiophene and benzothiophene hydroxamic acid derivatives
US7998957Feb 6, 2008Aug 16, 2011Lixte Biotechnology, Inc.Oxabicycloheptanes and oxabicylcoheptenes, their preparation and use
US8058268Jul 29, 2009Nov 15, 2011Lixte Biotechnology, Inc.Neuroprotective agents for the prevention and treatment of neurodegenerative diseases
US8088951Nov 30, 2007Jan 3, 2012Massachusetts Institute Of TechnologyEpigenetic mechanisms re-establish access to long-term memory after neuronal loss
US8143445Oct 1, 2008Mar 27, 2012Lixte Biotechnology, Inc.HDAC inhibitors
US8227473Jul 17, 2009Jul 24, 2012Lixte Biotechnology, Inc.Oxabicycloheptanes and oxabicycloheptenes, their preparation and use
US8227636Apr 5, 2005Jul 24, 2012Merck Hdac Research, LlcHistone deacetylase inhibitor prodrugs
US8263547May 28, 2009Sep 11, 2012Massachusetts Institute Of TechnologyDISC-1 pathway activators in the control of neurogenesis
US8329719Aug 1, 2011Dec 11, 2012Lixte Biotechnology, Inc.Neuroprotective agents for the prevention and treatment of neurodegenerative diseases
US8426444Jun 30, 2011Apr 23, 2013Lixte Biotechnology, Inc.Oxabicycloheptanes and oxabicycloheptenes, their preparation and use
US8455688Mar 21, 2012Jun 4, 2013Lixte Biotechnology, Inc.HDAC inhibitors
US8541458Jun 11, 2012Sep 24, 2013Lixte Biotechnology, Inc.Oxabicycloheptanes and oxabicycloheptenes, their preparation and use
US8563615Nov 1, 2010Oct 22, 2013Massachusetts Institute Of TechnologyUse of CI-994 and dinaline for the treatment of memory/cognition and anxiety disorders
US8822461Apr 19, 2013Sep 2, 2014Lixte Biotechnology, Inc.Oxabicycloheptanes and oxabicycloheptenes, their preparation and use
US8841346Aug 27, 2012Sep 23, 2014Massachusetts Institute Of TechnologyUse of CI-994 and dinaline for the treatment of memory/cognition and anxiety disorders
US9079917Jul 10, 2014Jul 14, 2015Lixte Biotechnology, Inc.Oxabicycloheptanes and oxabicycloheptenes, their preparation and use
US9115053Jul 20, 2012Aug 25, 2015Massachusetts Institute Of TechnologyActivators of class I histone deacetlyases (HDACS) and uses thereof
US20040002506 *Oct 25, 2002Jan 1, 2004Sloan Kettering Institute For Cancer ResearchNovel class of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof
US20040077591 *Mar 27, 2003Apr 22, 2004The Brigham And Women's Hospital, Inc.Histone deacetylase inhibitors for the treatment of multiple sclerosis, amyotrophic lateral sclerosis and Alzheimer's Disease
US20040266818 *Apr 1, 2004Dec 30, 2004Ronald BreslowHydroxamic acid compounds and methods of use thereof
US20050075282 *Oct 1, 2004Apr 7, 2005Douglas CoulterMaterials and methods for inhibiting the development of epilepsy
US20050137232 *Mar 17, 2004Jun 23, 2005Syrrx, Inc.Histone deacetylase inhibitors
US20050137234 *Dec 14, 2004Jun 23, 2005Syrrx, Inc.Histone deacetylase inhibitors
US20050159470 *Dec 14, 2004Jul 21, 2005Syrrx, Inc.Histone deacetylase inhibitors
US20050197336 *Nov 17, 2004Sep 8, 2005Miikana Therapeutics CorporationInhibitors of histone deacetylase
US20050250784 *Mar 8, 2005Nov 10, 2005Miikana Therapeutics CorporationInhibitors of histone deacetylase
US20060079551 *Nov 18, 2005Apr 13, 2006Richon Victoria MTreatment of neurodegenerative diseases and cancer of the brain using histone deacetylase inhibitors
US20060205941 *Dec 16, 2005Sep 14, 2006Bressi Jerome CHistone deacetylase inhibitors
US20060241129 *Jun 22, 2006Oct 26, 2006Ronald BreslowNovel class of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof
US20060258694 *May 10, 2006Nov 16, 2006Bressi Jerome CHistone deacetylase inhibitors
US20070010536 *Jun 22, 2006Jan 11, 2007Ronald BreslowNovel class of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof
US20070015809 *Jul 13, 2006Jan 18, 2007Bressi Jerome CHistone deacetylase inhibitors
US20070155785 *Feb 22, 2007Jul 5, 2007Ronald BreslowHydroxamic acid compounds and methods of use thereof
US20070173527 *Jan 12, 2007Jul 26, 2007Bressi Jerome CHistone deacetylase inhibitors
US20070213392 *Oct 8, 2004Sep 13, 2007Miller Thomas AThiophene and Benzothiophene Hydroxamic Acid Derivatives
US20080108829 *Oct 31, 2007May 8, 2008Bressi Jerome CHistone deacetylase inhibitors
US20080114037 *Oct 31, 2007May 15, 2008Bressi Jerome CHistone deacetylase inhibitors
US20080119648 *Oct 31, 2007May 22, 2008Bressi Jerome CHistone deacetylase inhibitors
US20080119658 *Oct 31, 2007May 22, 2008Bressi Jerome CHistone deacetylase inhibitors
US20080139535 *Jan 24, 2008Jun 12, 2008Miikana TherapeuticsInhibitors of histone deacetylase
US20080214569 *Feb 6, 2007Sep 4, 2008Zhengping ZhuangUse of phosphatases to treat tumors overexpressing N-CoR
US20080249179 *Oct 30, 2007Oct 9, 2008Bacopoulos Nicholas GMethods of treating cancer with HDAC inhibitors
US20090018142 *Feb 6, 2007Jan 15, 2009Zhengping ZhuangUse of phosphatases to treat tumors overexpressing N-CoR
US20090023718 *Nov 23, 2004Jan 22, 2009Aton Pharma, Inc.Diamine and Iminodiacetic Acid Hydroxamic Acid Derivatives
US20090023786 *Apr 5, 2005Jan 22, 2009Alton Pharma, Inc.Histone Deacetylase Inhibitor Prodrugs
US20090035292 *Aug 1, 2008Feb 5, 2009Kovach John SUse of phosphatases to treat neuroblastomas and medulloblastomas
US20090036309 *Feb 6, 2008Feb 5, 2009Kovach John SOxabicycloheptanes and oxabicylcoheptenes, their preparation and use
US20090054720 *Oct 8, 2008Feb 26, 2009George SgourosUse of histone deacetylase inhibitors in combination with radiation for the treatment of cancer
US20090111996 *Oct 31, 2007Apr 30, 2009Bressi Jerome CHistone deacetylase inhibitors
US20090143445 *Oct 1, 2008Jun 4, 2009John P. White, EsqHDAC Inhibitors
US20090325862 *Apr 30, 2007Dec 31, 2009Christian SteinkuhlerHistone Deacetylase Inhibitors for the Treatment of Neurodegeneration
US20100029484 *Jul 17, 2009Feb 4, 2010Kovach John SOxabicycloheptanes and oxabicycloheptenes, their preparation and use
US20100029640 *Jul 29, 2009Feb 4, 2010Lixte Biotechnology, Inc.Neuroprotective agents for the prevention and treatment of neurodegenerative diseases
US20100029683 *Jul 17, 2009Feb 4, 2010Kovach John SMethods for regulating cell mitosis by inhibiting serine/threonine phosphateses
US20100075926 *Jul 23, 2009Mar 25, 2010Li-Huei TsaiActivation of histone deacetylase 1 (hdac1) protects against dna damage and increases neuronal survival
US20100093867 *Jul 5, 2007Apr 15, 2010Ryoichi MatsudaMethod Of Treating Genetic Disease Caused By Nonsense Mutation
US20100113602 *Feb 27, 2008May 6, 2010The United States Of America,As Represented By The Secretary,Department Of Health And Human ServicesUse of histone deacetylase inhibitors for the treatment of central nervous system metastases
US20100278730 *Apr 8, 2008Nov 4, 2010Sabrina RonenNon-Invasive Molecular Imaging of Cellular Histone Deacetylase Substrate Using Magnetic Resonance Spectroscopy (MRS) or Positron Emission Tomography (PET)
US20110009475 *Jul 11, 2008Jan 13, 2011Massachusetts Institute Of TechnologyMethods for treating stress induced emotional disorders
US20110124731 *Jan 31, 2011May 26, 2011Sloan-Kettering Institute For Cancer ResearchTreatment Of Neurodegenerative Diseases And Cancer Of The Brain Using Histone Deacetylase Inhibitors
US20110224303 *Nov 1, 2010Sep 15, 2011Li-Huei TsaiUse of ci-994 and dinaline for the treatment of memory/cognition and anxiety disorders
EP3103791A1Jun 24, 2008Dec 14, 2016Merck Sharp & Dohme Corp.4-carboxybenzylamino derivatives as histone deacetylase inhibitors
WO2009002495A1Jun 24, 2008Dec 31, 2008Merck & Co., Inc.4-carboxybenzylamino derivatives as histone deacetylase inhibitors
WO2013066836A1 *Oct 30, 2012May 10, 2013Glaxosmithkline LlcCompounds and methods
Classifications
U.S. Classification514/575
International ClassificationA61P27/02, A61K31/4706, A61P35/00, A61P25/00, C07D213/75, A61P43/00, A61P21/04, C12N9/99, A61P25/08, A61K31/167, C07D215/40, A61P25/14, A61P25/16, A61P25/28, A61K31/00, A61K31/4709, A61K31/47, A61K31/4406, A61K31/19, A61K31/166, A61K31/16
Cooperative ClassificationA61K31/4406, A61K31/00, A61K31/16, A61K31/19, A61K31/4709, A61K31/47, A61K31/167, A61K31/166
European ClassificationA61K31/00, A61K31/167, A61K31/19, A61K31/16, A61K31/47, A61K31/4709, A61K31/4406, A61K31/166
Legal Events
DateCodeEventDescription
Sep 8, 2003ASAssignment
Owner name: SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH, NEW
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:RICHON, VICTORIA M.;MARKS, PAUL A.;RIFKIND, RICHARD A.;REEL/FRAME:014461/0971;SIGNING DATES FROM 20030212 TO 20030827
Jan 13, 2004ASAssignment
Owner name: SLOAN-KETTING INSTITUTE FOR CANCER RESEARCH, NEW Y
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:RICHON, VICTORIA A.;MARKS, PAUL A.;RIFKIND, RICHARD A;REEL/FRAME:014883/0454;SIGNING DATES FROM 20030212 TO 20030827