Sloan-kettering Institute for Cancer Research

Columbia University

Other

The Trustees of Columbia

Richard A Rifkind

Paul A Marks

Ronald C Breslow

Victoria M Richon

Branko Jursic

Thomas Allen Miller

Sandro Belvedere

Leland J Gershell

Xianbo Zhou

Nikola P Pavletich

Michael Finnin

Jill Donigian

Sandro Pontremoli

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.

Treatment of cancer of the brain using histone deacetylase inhibitors

The present invention features, inter alia, purified antibodies that selectively bind an isolated or recombinant histone deacetylase polypeptide comprising the amino acid sequence as set forth in SEQ ID NO: 2, which comprises a histone deacetylase catalytic domain at amino acids 635 to 953 of SEQ ID NO: 2, purified antibodies that selectively bind a biologically active fragment of the polypeptide of SEQ ID NO: 2, which fragment exhibits histone deacetylase activity, transcription repression activity, and the ability to deacetylate cellular substrates, purified antibodies that selectively bind an isolated or recombinant histone deacetylase polypeptide encoded by a nucleotide sequence as set forth in SEQ ID NO: 1, purified antibodies that selectively bind an isolated or recombinant histone deacetylase polypeptide comprising the amino acid sequence as set forth in SEQ ID NO: 2 lacking a nuclear localization signal, and purified antibodies that selectively bind an isolated or recombinant histone deacetylase polypeptide having at least 95% amino acid sequence identity to SEQ ID NO: 2 and which exhibits histone deacetylase activity, transcription repression activity, and the ability to deacetylate cellular substrates.

Antibodies that selectively bind HDAC9

The present invention relates to a novel class of hydroxamic acid derivatives having at least two aryl containing groups, at least one of which is a quinolinyl, isoquinolinyl or benzyl moiety, linked to the hydroxamic acid group through a methylene chain. The hydroxamic acid compounds can be used to treat cancer, for example, brain cancer. The hydroxamic acid compounds can also inhibit histone deacetylase and are suitable for use in selectively inducing terminal differentiation, and arresting cell growth and/or apoptosis of neoplastic cells, thereby inhibiting proliferation of such cells. Thus, the compounds of the present are useful in treating a patient having a tumor characterized by proliferation of neoplastic cells. The compounds of the invention are also useful in the prevention and treatment of TRX-mediated diseases, such as autoimmune, allergic and inflammatory diseases, and in the prevention and/or treatment of diseases of the central nervous system (CNS), such as neurodegenerative diseases.

Hydroxamic acid compounds and methods of use thereof

The present invention provides the compound having the formula: wherein each of Rand Ris, substituted or unsubstituted, aryl, cycloalkyl, cycloalkylamino, naphtha, pyridineamino, piperidino, t-butyl, aryloxy, arylalkyloxy, or pyridine group; wherein A is an amido moiety, &#x2014;O&#x2014;, &#x2014;S&#x2014;, &#x2014;NH&#x2014;, or &#x2014;CH&#x2014;; and wherein n is an integer from 3 to 8. The present invention also provides a method of selectively inducing growth arrest, terminal differentiation and/or apoptosis of neoplastic cells and thereby inhibiting proliferation of such cells. Moreover, the present invention provides a method of treating a patient having a tumor characterized by proliferation of neoplastic cells. Lastly, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically acceptable amount of the compound above.

Cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof

The present invention features substantially pure HDAC9, HDAC9a, HDAC9(&#x394;NLS), HDAC9a(&#x394;NLS), an HDRP(&#x394;NLS) polypeptides, and isolated nucleic acid molecules encoding those polypeptides. The present invention also features vectors containing HDAC9, HDAC9a, HDAC9(&#x394;NLS), HDAC9a(&#x394;NLS), and HDRP(&#x394;NLS) nucleic acid sequences, and cells containing those vectors.

HDAC9 polypeptides and polynucleotides and uses thereof

Class of cytodifferentiating agents and histone deacetylase inhibitors, and methods of use thereof

The present invention provides three-dimensional structural information from the hyperthermophilic bacteriumwhich is a histone deacetylase-like protein (HDLP). HDLP shares 35.2% amino acid sequence identity with human histone deacetylase (HDAC1). The present invention further provides three-dimensional structural information of HDLP bound by inhibitor molecules. The three-dimensional structural information of the present invention is useful to design, isolate and screen deacetylase inhibitor compounds capable of inhibiting HDLP, HDAC family members and HDLP-related molecules. The invention also relates to nucleic acids encoding a mutant HDLP which facilitates the determination of the three-dimensional structure of HDLP in the presence of a zinc atom.

Crystal structure of a deacetylase and inhibitors thereof

Potent inducers of terminal differentiation and methods of use thereof

The present invention provides the compound having the structure: ##STR1## wherein each of R.sub.1 and R.sub.2 are independently the same as or different from each other; when R.sub.1 and R.sub.2 are the same, each is a substituted or unsubstituted arylamino, cycloalkylamino, pyridineamino, piperidino, 9-purine-6-amine, or thiozoleamino group; when R.sub.1 and R.sub.2 are different, R.sub.1 =R.sub.3 --N--R.sub.4, wherein each of R.sub.3 and R.sub.4 are independently the same as or different from each other and are a hydrogen atom, a hydroxyl group, a substituted or unsubstituted, branched or unbranched alkyl, alkenyl, cycloalkyl, aryl, alkyloxy, aryloxy, arylalkyloxy, or pyridine group, or R.sub.3 and R.sub.4 bond together to form a piperidine group and R.sub.2 is a hydroxylamino, hydroxyl, amino, alkylamino, dialkylamino or alkyloxy group; and n is an integer from about 4 to about 8. The present invention also provides a method of selectively inducing terminal differentiation of neoplastic cells and thereby inhibiting proliferation of such cells. Moreover, the present invention provides a method of treating a patient having a tumor characterized by proliferation of neoplastic cells. Lastly, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically acceptable amount of the compound above.

The invention provides compounds, several of which belong to a class having two or more nonpolar components connected by a polar group and having polar groups on the termini of the compound. The invention also concents a method of selectively inducing termini differentiation of neoplastic cells and thereby inhibiting proliferation of such cells which comprises contacting the cells under suitable condition with an amount of the compound effective to selectively induce terminal differentiation. Moreover, the invention provides a method of treating a patient having a tumor characterized by proliferation of neoplastic cells which comprises administering to the patient an amount of the compound effective to selectively induce terminal differentiation of such neoplastic cells, thereby inhibiting their proliferation and suppressing oncogenicity. Lastly, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound in an amount effective less than an amount which would cause toxicity in the patient.

Potent inducers of terminal differentiation and method of use thereof

The invention provides a class of compounds and compositions thereof having the structure: ##STR1## wherein A is: ##STR2## The invention also concerns a method of selectively inducing terminal differentiation of neoplastic cells thereby inhibiting proliferation of such cells which comprises contacting the cells under suitable conditions with an amount of the compound to selectively induce terminal differentiation. It also provides a method of treating a patient having a tumor characterized by proliferatoin of neoplastic cells comprising administration of an amount of the compound effective to inhibit proliferation and suppress oncogenicity of neoplastic cells.

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New York, NY, United States of America

Richard A Rifkind