498 results about "Histone deacetylase inhibitor" patented technology

Compositions and methods are provided for treating diseases associated with aberrant silencing of gene expression such as cancer by reestablishing the gene expression through inhibition of DNA hypomethylation and histone deacetylase. The method comprises: administering to a patient suffering from the disease a therapeutically effective amount of a DNA methylation inhibitor such as a cysteine analog such as decitabine, in combination with an effective amount of histone deacetylase inhibitor such as hydroxamic acid, cyclic peptide, benzamide, butyrate, and depudecin.

The invention provides novel classes of HDAC inhibitors. Methods of sensitizing a cancer cell to the cytotoxic effects of radiotherapy are also provided as well as methods for treating cancer and methods for treating neurological diseases. Additionally, the invention further provides pharmaceutical compositions comprising an HDAC inhibitor of the invention, and kits comprising a container containing an HDAC inhibitor of the invention.

Compositions and methods for treatment of conditions related to the overexpression of EZH2, such as late stage prostate cancer, using a DNA methylation inhibitor and/or a histone deacetylase inhibitor, optionally in combination with an EZH2 antagonist and/or an antineoplastic agent, to specifically target diseases associated with EZH2 over-expression. Further provided are reagents and kits for treatment of EZH2 overexpression.

The present invention relates to the enhancement of cognition in an individual by delivery of a histone acetylation regulator, such as a histone deacetylase inhibitor. The individual may have normal or poor memory, and the poor memory may be the result of a pathogenic condition or a non-pathogenic condition, such as with normal aging-related impairment. In a specific embodiment, enhancement of cognition occurs in an individual having a mental retardation syndrome.

Compositions, kits and methods are provided for treating or preventing neurological disorders associated with aberrant silencing of gene expression by reestablishing the gene expression through inhibition of DNA methylation and/or histone deacetylase. The compositions and methods include administering to a patient suffering from the neurological disorder a therapeutically effective amount of a DNA methylation inhibitor, such as decitabine, preferably in combination with an effective amount of a histone deacetylase inhibitor. The compositions, kits and methods can be used to treat or present neurological disorders such as Lou Gehrig's disease, fragile X syndrome, Parkinson's disease and Alzheimer's disease.

This invention is related to new histone deacetylase inhibitors according to the general formula (I) wherein: the dotted line is an optional additional bond; n is zero or an integer from 1 to 4; R¹ is hydrogen; C₁-C₆ alkyl, optionally substituted by cycloalkyl, aryl or by heteroaryl; (CO)R³; (SO₂)R⁴; cycloalkyl; aryl; or heteroaryl; R² is C₁-C₆ alkyl, optionally substituted by aryl or by heteroaryl; aryl; heteroaryl; or (CO)R⁵; X is CH₂, oxygen or NR⁶; Y is a bond, CHR⁷ or NR⁸; Z is oxygen, CR⁹R¹⁰ or C═R¹¹; and R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are as further defined in the specification; and pharmaceutical acceptable salts thereof.

The present invention relates to an orally available galenics formulation of Valproic Acid or derivatives thereof exhibiting a specific bi-phasic pharmacokinetic profile optimized for maximum inhibition of histone deacetylases in a therapeutic setting. This specific galenics formulation is designed for the treatment of malignant diseases and diseases associated with hypoacetylation of histones or in which induction of hyperacetylation has a beneficial effect, e.g., by induction of differentiation and/or apoptosis. Due to the bi-phasic release pattern the resulting pharmacokinetic profile is able to inhibit HDAC target enzymes most efficiently and to subsequently induce histone hyperacetylation in a rapid as well as a long-lasting fashion. This profile secures the efficient modulation of a desired target gene expression profile which contributes to the therapeutic benefit.

Compounds of formula (I), and salts, N-oxides, hydrates and solvates thereof are histone deacetylase inhibitors and are useful in the treatment of cell proliferative diseases, including cancers:

wherein Q, V and W independently represent —N═ or —C═; B is a divalent radical selected from (B1), (B2), (B3), (B4), (B5) and (B6).

wherein the bond marked * is linked to the ring containing Q, V and W through -[Linker1]- and the bond marked ** is linked to A through -[Linker2]-; A is an optionally substituted mono-, bi- or tri-cyclic carbocyclic or heterocyclic ring system; -[Linker1]- and -[Linker2]- independently represent a bond, or a divalent linker radical; and R is (a) a radical of formula R₁R₂CHNH—Y-L¹-X¹—(CH₂)_z— or (b) a radical of formula R-L¹-Y¹—(CH₂)_z—,

The present invention provides compositions and methods for increasing therapeutic gain in radiotherapy and chemotherapy for proliferating malignant or nonmalignant disease to produce high probability of tumor control with low frequency of sequelae of therapy by administering a therapeutically effective amount of a histone deacetylase inhibitor. The compounds are capable of simultaneously stimulating the epithelium regrowth, inhibiting the fibroblast proliferation, decreasing the collagen deposit, suppressing the fibrogenic growth factor, subsiding the proinflammatory cytokine and modulating the expression of cell cycle genes, tumor suppressors and oncogenes, and are useful to increase the therapeutic gain in radiotherapy and chemotherapy, which results in decrease of skin swelling and inflammation, promotion of epithelium healing in mucosa and dermis, decrease of xerostomia, prevention/reduction of severity of plantar-palmar syndrome, prevention of tissue fibrosis, ulceration, necrosis and tumorigenesis, and increase of tumor growth inhibition and tumor therapy effectiveness.

The present disclosure relates to inhibitors of zinc-dependent histone deacetylases (HDACs) useful in the treatment of diseases or disorders associated with an HDAC, e.g., HDAC6, having a Formula I:

where R, L, X¹, X², X³, X⁴, Y¹, Y², Y³, and Y⁴ are described herein.

The present disclosure relates to inhibitors of zinc-dependent histone deacetylases (HDACs) useful in the treatment of diseases or disorders associated with an HDAC, e.g., HDAC6, having a Formula I:

where R, L, X¹, X², X³, X⁴, Y¹, Y², Y³, and Y⁴ are described herein.

The present invention relates to compounds of formula (I):

or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein U, J, V, X, R^2a, R^2b, R^2c, R⁵ and t are as described herein. The present invention relates generally to inhibitors of histone deacetylase and to methods of making and using them. These compounds are useful for promoting cognitive function and enhancing learning and memory formation. In addition, these compounds are useful for treating, alleviating, and/or preventing various conditions, including for example, neurological disorders, memory and cognitive function disorders/impairments, extinction learning disorders, fungal diseases and infections, inflammatory diseases, hematological diseases, and neoplastic diseases in humans and animals.

Disclosed herein are novel approaches to thyroid cancer therapy. These approaches include methods to enhance thyroid specific gene expression, for example methods to enhance expression of thyroglobulin and/or the Na<+>/I<-> symporter in thyroid cancer cells. Enhanced expression of thyroid-specific genes promotes cellular differentiation and reduces biologically aggressive behavior such as invasion and metastasis. In addition, enhanced expression of thyroglobulin and/or the Na<+>/I<31 > symporter increases the ability of thyroid cancer cells to concentrate iodine or iodide, thereby making the cells more susceptible to radioactive iodine therapy. Also disclosed herein are methods for detecting thyroid neoplasms in a subject, by administering a therapeutically effective amount of a histone deacetylase inhibitor, administering a detectable agent whose uptake or concentration in thyroid cells is increased by administration of the histone deacetylase inhibitor, and detecting the detectable agent.

The present invention relates to reduced FK228 of the formula (I)

wherein R¹ and R² are the same or different and each is a hydrogen atom or a thiol-protecting group, or a salt thereof, and a histone deacetylase inhibitor containing this compound, an expression potentiator and a reactivation promoter of a transgene, and pharmaceutical agents containing them as active ingredients. The reduced FK228 or a salt thereof has a strong histone deacetylase inhibitory activity and this compound can be used for the prophylaxis or treatment of various diseases, in which histone deacetylation is involved, and for the gene therapy of such diseases.

The present invention relates to hydroxamate compounds which are inhibitors of histone deacetylase. More particularly, the present invention relates to benzimidazole containing compounds and methods for their preparation. These compounds may be useful as medicaments for the treatment of proliferative disorders as well as other diseases involving, relating to or associated with dysregulation of histone deacetylase (HDAC).

The present invention is directed to prodrugs of hydroxamic acid based histone deacetylase (HDAC) inhibitors, e.g., suberoylanilide hydroxamic acid (SAHA). The prodrugs are acylated derivatives having increased aqueous solubility and cellular permeability as compared with the free hydroxamic acid, and are useful for inhibiting HDACs, and for selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, thereby inhibiting proliferation of such cells. Thus, the prodrugs of the present invention are useful in treating a patient having a tumor characterized by proliferation of neoplastic cells. The prodrugs of the invention are also useful in the prevention and treatment of thioredoxin (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.

The invention relates to combinations comprising an HDAC inhibitor and an immunomodulatory drug for the treatment of lymphoma in a subject in need thereof. Also provided herein are methods for treating lymphoma in a subject in need thereof comprising administering to the subject an effective amount of one of the above combinations.

The present invention is related to the preparation and pharmaceutical use of novel benzamide derivatives as defined in the specification of formula (I) as histone deacetylase inhibitors (HDACI), their preparations and the methods of using these compounds or their pharmaceutically acceptable salt in the treatment of cell proliferative diseases, e.g. cancer and psoriasis

An antitumor agent containing, in combination, at least one kind of antitumor agent selected from the group consisting of an antitumor agent that forms a cross-link with DNA and shows an antitumor effect, an antimetabolite antitumor agent and a taxane antitumor agent, and a histone deacetylase inhibitor. According to the present invention, an antitumor agent causing reduced side effects and having a superior antitumor activity can be provided.