225 results about "Hsp Inhibitor" patented technology

Novobiocin analogues useful as Hsp90 inhibitors in the treatment of cancer, neuroprotection, and autoimmune disorders.

Pyrrolopyrimidines and related analogs are described and demonstrated to have utility as Heat Shock Protein 90 (HSP90) inhibiting agents used in the treatment and prevention of various HSP90 mediated disorders, e.g., proliferative disorders. Methods of synthesis and use of such compounds are also described and claimed.

The invention provides purified 18,21-didehydro-18,21-dideoxo-18,21-dihydroxy-geldanamycin derivatives, pharmaceutically acceptable salts thereof and prodrugs thereof that are potent Hsp90 binding agents that are useful for the treatment and / or the amelioration of symptoms of cancer and other proliferative tissue disorders.

Hsp90 inhibitors are provided having the formula:with a 2′,4′,5′-substitution pattern on the right-side aryl moiety. X1 represents two substituents, which may be the same or different, disposed in the 4′ and 5′ positions on the aryl group, wherein X1 is selected from halogen, alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, amido, alkylamido dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, SO2−alkyl, COO-alkyl, KH2, OH, CN, SO2X5, NO2, NO, C═SR2 NSO2X5, C═OR2, where X5 is F, NH2, alkyl or H, and R2 is alkyl, NH2, NH-alkyl or O-alkyl, C1 to C6 alkyl or alkoxy; or wherein X1 has the formula —O—(CH2)n—O—, wherein n is an integer from 0 to 2, preferably 1 or 2, and one of the oxygen is bonded at the 5′-position and the other at the 4′-position of the aryl ring. The compounds are useful in cancer therapy and as radioimaging ligands.

The present invention concerns methods and compositions involving MDA-7 protein or an MDA-7-encoding nucleic acid in combination with either 1) a COX-2 selective inhibitor, such as celecoxib, 2) an Hsp90 inhibitor, such as geldanamycin, or a geldanamycin derivative or analog, 3) a vitamin E compound, for the treatment of cancer, 4) a TNF, such as TNF-alpha, 5) a VEGF inhibitor, or 6) an inhibitor of IL-10. In certain examples, a treatment for breast cancer is provided. In other examples a treatment for lung cancer is provided. Such examples involve, in some cases, an adenovirus vector that expresses MDA-7 protein.

The present invention relates to HSP90 inhibitors and their use in the treatment of cell proliferative diseases such as cancer. The said derivatives may further act as HDAC inhibitors.

The present invention provides a method for treating cancer. The method involves the administration of an HSP90 inhibitor and an enzyme inhibitor, where the combined administration provides a synergistic effect. In one aspect of the invention, a method of treating cancer is provided where a subject is treated with a dose of an HSP90 inhibitor in one step and a dose of an enzyme inhibitor in another step. In another aspect of the invention, a method of treating cancer is provided where a subject is first treated with a dose of an HSP90 inhibitor and subsequently treated with a dose of an enzyme inhibitor. In another aspect of the invention, a method of treating cancer is provided where a subject is first treated with a dose of an enzyme inhibitor and subsequently treated with a dose of an HSP90 inhibitor.

The present invention relates to HSP90 inhibitors containing fused amino pyridine core that are useful as inhibitors of HSP90 and their use in the treatment of HSP90 related diseases and disorders such as cancer, an autoimmune disease, or a neurodegenerative disease.

Triazolopyrimidines and related compounds are described and demonstrated or predicted to have utility as Heat Shock Protein 90 (HSP90) inhibiting agents in the treatment and prevention of various HSP90 mediated disorders, e.g., proliferative disorders. Method of synthesis and use of such compounds are also described and claimed.

The present invention provides a method for treating cancer. The method involves the administration of an HSP90 inhibitor and an immunosuppressant, where the combined administration provides a synergistic effect. In one aspect of the invention, a method of treating cancer is provided where a subject is treated with a dose of an HSP90 inhibitor in one step and a dose of an immunosuppressant in another step. In another aspect of the invention, a method of treating cancer is provided where a subject is first treated with a dose of an HSP90 inhibitor and subsequently treated with a dose of an immunosuppressant. In another aspect of the invention, a method of treating cancer is provided where a subject is first treated with a dose of an immunosuppressant and subsequently treated with a dose of an HSP90 inhibitor.

The process of the invention relates to a kit of two cosmetic, pharmaceutical, veterinary and food compositions, designed for slimming or for preventing and / or repairing inflammatory mechanisms, one of the compositions comprising at least one sirtuin activator and at least one HSP activator, and the other composition comprising at least one sirtuin inhibitor and at least one HSP inhibitor.The said compositions are intended to be delivered in a chronomodulated pattern. They are particularly effective in combination with one another for controlling fat tissues, adipose, fibrous or aqueous cellulite, cell aging and inflammatory processes.

Hsp90 inhibitors are provided having the formula:with a 2′,4′,5′-substitution pattern on the right-side aryl moiety. X1 represents two substituents, which may be the same or different, disposed in the 4′ and 5′ positions on the aryl group, wherein X1 is selected from halogen, alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, amido, alkylamido dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, SO2. alkyl, COO-alkyl, KH2, OH, CN, SO2X5, NO2, NO, C═SR2 NSO2X5, C═OR2, where X5 is F, NH2, alkyl or H, and R2 is alkyl, NH2, NH-alkyl or O-alkyl, C1 to C6 alkyl or alkoxy; or wherein X1 has the formula -0-(CH2)n-0-, wherein n is an integer from O to 2, preferably 1 or 2, and one of the oxygens is bonded at the 5′-position and the other at the 4′-position of the aryl ring. The compounds are useful in cancer therapy and as radioimaging ligands.

The present invention provides pharmacological compounds including an effector moiety conjugated to an binding moiety that directs the effector moiety to a biological target of interest. Likewise, the present invention provides compositions, kits, and methods (e.g., therapeutic, diagnostic, and imaging) including the compounds. The compounds can be described as a protein interacting binding moiety-drug conjugate (SDC-TRAP) compounds, which include a protein interacting binding moiety and an effector moiety. For example, in certain embodiments directed to treating cancer, the SDC-TRAP can include an Hsp90 inhibitor conjugated to a cytotoxic agent as the effector moiety.

The present invention relates to compounds according to formulae (IA) to (ID) and compositions that inhibit the activity of Hsp90. The invention further relates to methods of inhibiting the activity of Hsp90 in a subject in need thereof and methods for preventing or treating hyperproliferative disorders, such as cancer, in a subject in need thereof comprising administering to the subject a compound of the invention, or a composition comprising such a compound.

Provided is a method for treating non-small cell lung cancer with wild-type EGFR gene and / or KRAS gene by administering to a subject in need thereof, an effective amount of a triazolone compound according to the following formula:a tautomer, or a pharmaceutically acceptable salt thereof, wherein the variables in the structural formulae are defined herein.

Purine scaffold Hsp90 inhibitors are useful in therapeutic applications and as radioimaging ligands.

The administration of cytotoxic agents followed by the administration of heat shock protein 90 inhibitors, such as ansamycins, has a synergistic effect on the growth inhibition of cells. This synergy occurs at doses of each cytotoxic agent that normally only causes minimal growth inhibition of cells. Such combination therapy thus allows one to use lower doses of cytotoxic agents to avoid or reduce their respective toxicity to patients without compromising their growth inhibitory effects. Thus, these combinations can be used for the treatment of an animal, preferably a mammal, that has a cell proliferative disorder, whether the cells have wild-type Rb or are Rb deficient or Rb negative. One such method, directed to treating cell proliferative disorders includes the step of administering a therapeutic effective amount of a cytotoxic agent followed by administering a therapeutic effective amount of a heat shock protein 90 inhibitor. The cytotoxic agent may be a microtubule-affecting agent, topoisomerase II inhibitor, a platinum complex, paclitaxel, or a paclitaxel derivative. The HSP90 inhibitor may be an ansamycin, radicicol or a synthetic compound that binds to the ATP-binding site of HSP90.

A pharmaceutical combination comprising a topoisomerase II inhibitor, and an Hsp90 inhibitor according to the following formulae a tautomer, or a pharmaceutically acceptable salt thereof, wherein the variables in the structural formulae are defined herein. Also provided is a method for treating a proliferative disorder in a subject in need thereof, using the pharmaceutical combination described herein.

The disclosure provides novobiocin analogues with noviose replacements which are useful as Hsp90 inhibitors in the treatment of cancer.

This invention provides methods and compositions for screening of microRNA capable of modulating gene expression in the apoptotic pathway in the presence of HSP90 inhibitor. The use of miRNA for enhancing the activity of therapeutic agents not limited to HSP90 inhibitor is also disclosed. The diagnostic use of miRNA for predicting response to therapy not limited to therapeutic agents is also disclosed. A method for the identification and therapeutic application of small molecules which are modulators of these nucleic acids are also included in this application.

Novobiocin analogues useful as Hsp90 inhibitors in the treatment of cancer, neuroprotection, and autoimmune disorders.

This invention relates to a method for treatment of latent Toxoplasma gondii infection. The invention provides for the use of Hsp90 inhibitors for treatment of latent Toxoplasma gondii infection, particularly in an immunocompromised subject. Also provided is a screening method for identifying compounds useful for treating latent Toxoplasma gondii infection.

Described herein are compositions, kits, and methods for determining whether subjects having cancer(s) are likely to respond to treatment with an HSP90 inhibitor, as a single agent or in combination therapy. Further described are methods for prognosing a time course of disease in a subject having such cancer.

Provided is a method of identifying Hsp90 inhibitors with substantially less ocular toxicity or with substantially improved ocular toxicity profile. The method comprises measuring the respective concentrations of an Hsp90 inhibitor in the retina and plasma at certain time points following the administration of the Hsp90 inhibitor in a subject, and determining the concentration ratio of the Hsp90 inhibitor between retina and plasma, where a certain ratio is indicative that the Hsp90 inhibitor has substantially less ocular toxicity. The method also includes identifying an Hsp90 inhibitor with substantially less ocular toxicity, or with a substantially improved ocular toxicity profile, by determining the elimination rate of the Hsp90 inhibitor from the retina following administration of the Hsp90 inhibitor, where a certain elimination rate is indicative that the Hsp90 inhibitor will induce substantially less ocular toxicity.

Disclosed is a triazole derivative(s) represented by the general formula (1) below or a pharmacologically acceptable salt(s) thereof. Also disclosed are a prodrug(s) of such a triazole derivative(s) and an HSP90 inhibitor(s) containing any one of them as an active constituent. (1) (In the formula, X represents a halogen atom, an optionally substituted alkyl group, an optionally substituted alkynyl group or the like; Y represents a mercapto group, a hydroxyl group, an optionally substituted sulfonyl group, an optionally substituted amino group or the like; and R represents an optionally substituted aryl or alkyl group or the like.)

The administration of cytotoxic agents followed by the administration of heat shock protein 90 inhibitors, such as ansamycins, has a synergistic effect on the growth inhibition of cells. This synergy occurs at doses of each cytotoxic agent that normally only causes minimal growth inhibition of cells. Such combination therapy thus allows one to use lower doses of cytotoxic agents to avoid or reduce their respective toxicity to patients without compromising their growth inhibitory effects. Thus, these combinations can be used for the treatment of an animal, preferably a mammal, that has a cell proliferative disorder, whether the cells have wild-type Rb or are Rb deficient or Rb negative. One such method, directed to treating cell proliferative disorders includes the step of administering a therapeutic effective amount of a cytotoxic agent followed by administering a therapeutic effective amount of a heat shock protein 90 inhibitor. The cytotoxic agent may be a microtubule-affecting agent, topoisomerase II inhibitor, a platinum complex, paclitaxel, or a paclitaxel derivative. The HSP90 inhibitor may be an ansamycin, radicicol or a synthetic compound that binds to the ATP-binding site of HSP90.

The disclosure provides evidence that the abundance of this particular “oncogenic HSP90” species, which is not dictated by HSP90 expression alone, predicts for sensitivity to HSP90 inhibition therapy, and thus is a biomarker for HSP90 therapy. The disclosure also provides evidence that identifying and measuring the abundance of this oncogenic HSP90 species in tumors predicts of response to HSP90 therapy. “Oncogenic HSP90” is defined herein as the HSP90 fraction that represents a cell stress specific form of chaperone complex, that is expanded and constitutively maintained in the tumor cell context, and that may execute functions necessary to maintain the malignant phenotype. Such roles are not only to regulate the folding of overexpressed (i.e. HER2), mutated (i.e. mB-Raf) or chimeric proteins (i.e. Bcr-Abl), but also to facilitate scaffolding and complex formation of molecules involved in aberrantly activated signaling complexes (i.e. STATS, BCL6).

Purine scaffold Hsp90 inhibitors are useful in therapeutic applications and as radioimaging ligands.

The present application provides compounds useful in the inhibition of Hsp90, and hence in the treatment of disease.