U.S. patent application number 10/273401 was filed with the patent office on 2004-05-06 for treatment of neurodegenerative diseases and cancer of the brain using histone deacetylase inhibitors.
Invention is credited to Marks, Paul A., Richon, Victoria M., Rifkind, Richard A..
Application Number | 20040087657 10/273401 |
Document ID | / |
Family ID | 23286625 |
Filed Date | 2004-05-06 |
United States Patent
Application |
20040087657 |
Kind Code |
A1 |
Richon, Victoria M. ; et
al. |
May 6, 2004 |
Treatment of neurodegenerative diseases and cancer of the brain
using histone deacetylase inhibitors
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.
Inventors: |
Richon, Victoria M.; (Rye,
NY) ; Marks, Paul A.; (Washington, CT) ;
Rifkind, Richard A.; (New York, NY) |
Correspondence
Address: |
IVOR R. ELRIFI, Esq.
MINTZ, LEVIN, COHN, FERRIS, GLOVSKY & POPEO, P.C.
ONE FINANCIAL CENTER
BOSTON
MA
02111
US
|
Family ID: |
23286625 |
Appl. No.: |
10/273401 |
Filed: |
October 16, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60329705 |
Oct 16, 2001 |
|
|
|
Current U.S.
Class: |
514/575 |
Current CPC
Class: |
A61K 31/4406 20130101;
A61K 31/16 20130101; A61K 31/19 20130101; A61K 31/166 20130101;
A61P 35/00 20180101; A61K 31/4709 20130101; A61P 25/16 20180101;
A61P 25/00 20180101; A61K 31/167 20130101; A61K 31/00 20130101;
A61K 31/47 20130101; A61P 21/04 20180101; A61P 25/08 20180101; A61P
27/02 20180101; A61P 25/14 20180101; A61P 25/28 20180101; A61P
43/00 20180101 |
Class at
Publication: |
514/575 |
International
Class: |
A61K 031/19 |
Claims
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: 678910or a pharmaceutically acceptable
salt thereof.
3. The method of claim 2, wherein the histone deacetylase inhibitor
compound is selected from: 11or 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: 1213141516or a pharmaceutically
acceptable salt thereof.
9. The method of claim 8, wherein the histone deacetylase inhibitor
compound is selected from: 17or 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: 1819202122or a pharmaceutically
acceptable salt thereof.
12. The method of claim 11, wherein the histone deacetylase
inhibitor is selected from: 23or 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] FIG. 1 is a scan of a Western blot and Coomassie stained gel
indicating levels of acetylated histone (.alpha.AcH3) at the
indicated timepoints following treatment with vehicle (DMSO) or
three doses of SAHA (100 mg/kg/hr).
[0008] FIG. 2 is a scan of a Western blot and Coomassie stained gel
indicating levels of acetylated histone (.alpha.AcH4) 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: 12345
[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 .mu.g) 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 (.alpha.Ac-H4) and anti-acetylated histone H3 antibody
(.alpha.Ac-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.
* * * * *