U.S. patent application number 13/017447 was filed with the patent office on 2011-05-26 for treatment of neurodegenerative diseases and cancer of the brain using histone deacetylase inhibitors.
This patent application is currently assigned to Sloan-Kettering Institute for Cancer Research. Invention is credited to Paul A. Marks, Victoria M. Richon, Richard A. Rifkind.
Application Number | 20110124731 13/017447 |
Document ID | / |
Family ID | 23286625 |
Filed Date | 2011-05-26 |
United States Patent
Application |
20110124731 |
Kind Code |
A1 |
Richon; Victoria M. ; et
al. |
May 26, 2011 |
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.;
(Wellesley, MA) ; Marks; Paul A.; (Washington,
CT) ; Rifkind; Richard A.; (New York, NY) |
Assignee: |
Sloan-Kettering Institute for
Cancer Research
New York
NY
|
Family ID: |
23286625 |
Appl. No.: |
13/017447 |
Filed: |
January 31, 2011 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
11282420 |
Nov 18, 2005 |
7879865 |
|
|
13017447 |
|
|
|
|
10273401 |
Oct 16, 2002 |
|
|
|
11282420 |
|
|
|
|
60329705 |
Oct 16, 2001 |
|
|
|
Current U.S.
Class: |
514/575 |
Current CPC
Class: |
A61K 31/19 20130101;
A61K 31/167 20130101; A61P 25/14 20180101; A61P 21/04 20180101;
A61K 31/00 20130101; A61P 27/02 20180101; A61K 31/166 20130101;
A61P 25/28 20180101; A61K 31/47 20130101; A61K 31/16 20130101; A61P
25/08 20180101; A61K 31/4406 20130101; A61P 35/00 20180101; A61K
31/4709 20130101; A61P 43/00 20180101; A61P 25/16 20180101; A61P
25/00 20180101 |
Class at
Publication: |
514/575 |
International
Class: |
A61K 31/167 20060101
A61K031/167; A61P 35/00 20060101 A61P035/00 |
Claims
1. A method of treating a brain cancer in a mammal comprising
administering to the mammal a therapeutically effective amount of
Suberoylanilide Hydroxamic Acid (SAHA), represented as:
##STR00006## or a pharmaceutically acceptable salt thereof.
2. The method of claim 1, wherein the Suberoylanilide Hydroxamic
Acid (SAHA) or a pharmaceutically acceptable salt thereof is
administered orally.
3. The method of claim 1, wherein the mammal is a human.
4. The method of claim 2, wherein SAHA is administered.
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.
Nos. 5,369,108, issued on Nov. 29, 1994, 5,700,811, issued on Dec.
23, 1997, and 5,773,474, issued on Jun. 30, 1998 to Breslow et al.,
U.S. Pat. Nos. 5,055,608; issued on Oct. 8, 1991, and 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. The individual can be a mammal
such as a primate or human.
BRIEF DESCRIPTION OF THE DRAWINGS
[0006] 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).
[0007] 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
[0008] 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.
[0009] The individual can be a mammal such as a primate or
human.
[0010] 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.
[0011] 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.
[0012] 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).
[0013] Generally, neurodegenerative diseases can be grouped as
follows: [0014] I. Disorders characterized by progressive dementia
in the absence of other prominent neurologic signs. [0015] A.
Alzheimer's disease [0016] B. Senile dementia of the Alzheimer type
[0017] C. Pick's disease (lobar atrophy) [0018] II. Syndromes
combining progressive dementia with other prominent neurologic
abnormalities [0019] A. Mainly in adults [0020] 1. Huntington's
disease [0021] 2. Multiple system atrophy combining dementia with
ataxia and/or manifestations of Parkinson's disease [0022] 3.
Progressive supranuclear aplsy (Steel-Richardson-Olszewski) [0023]
4. Diffuse Lewy body disease [0024] 5. Corticodentatonigral
degeneration [0025] B. Mainly in children or young adults [0026] 1.
Hallervorden-Spatz disease [0027] 2. Progressive familial myoclonic
epilepsy [0028] III. Syndromes of gradually developing
abnormalities of posture and movement [0029] A. Paralysis agitans
(Parkinson's disease) [0030] B. Striatonigral degeneration [0031]
C. Progressive supranuclear palsy [0032] D. Torsion dystonia
(torsion spasm; dystonia musculorum deformans) [0033] E. Spasmodic
torticollis and other dyskinesis [0034] F. Familial tremor [0035]
G. Gilles de la Tourette syndrome [0036] IV. Syndromes of
progressive ataxia [0037] A. Cerebellar degenerations [0038] 1.
Cerebellar cortical degeneration [0039] 2. Olivopontocerebellar
atrophy (OPCA) [0040] B. Spinocerebellar degeneration (Friedreich's
atazia and related disorders) [0041] V. Syndrome of central
autonomic nervous system failure (Shy-Drager syndrome) [0042] VI.
Syndromes of muscular weakness and wasting without sensory changes
(motor neuron disease [0043] A. Amyotrophic lateral sclerosis
[0044] B. Spinal muscular atrophy [0045] 1. Infantile spinal
muscular atrophy (Werdnig-Hoffman) [0046] 2. Juvenile spinal
muscular atrophy (Wohlfart-Kugelberg-Welander) [0047] 3. Other
forms of familial spinal muscular atrophy [0048] C. Primary lateral
sclerosis [0049] D. Hereditary spastic paraplegia [0050] VII.
Syndromes combining muscular weakness and wasting with sensory
changes (progressive neural muscular atrophy; chronic familial
polyneuropathies) [0051] A. Peroneal muscular atrophy
(Charcot-Marie-Tooth) [0052] B. Hypertrophic interstitial
polyneuropathy (Dejerine-Sottas) [0053] C. Miscellaneous forms of
chronic progressive neuropathy [0054] VIII Syndromes of progressive
visual loss [0055] A. Pigmentary degeneration of the retina
(retinitis pigmentosa) [0056] B. Hereditary optic atrophy (Leber's
disease)
[0057] HDAC inhibitors suitable for use in the invention include,
but are not limited to the following specific structures:
##STR00001## ##STR00002## ##STR00003## ##STR00004##
##STR00005##
[0058] 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.
Nos. 5,369,108, issued on Nov. 29, 1994, 5,700,811, issued on Dec.
23, 1997, and 5,773,474, issued on Jun. 30, 1998 to Breslow et al.,
U.S. Pat. Nos. 5,055,608, issued on-Oct. 8, 1991, and 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
[0059] 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 EP 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.
* * * * *