102 results about "Mdm2" patented technology

The invention relates to small molecules which function as inhibitors of the interaction between p53 and MDM2. The invention also relates to the use of these compounds for inhibiting cell growth, inducing cell death, inducing cell cycle arrest and / or sensitizing cells to additional agent(s).

MDM2 and MDM4 proteins prevent apoptosis of cancer cells by negatively regulating the transcription factor p53. Compounds according to Formula Iare selective antagonists of MDM2 and MDM4 proteins, disrupting the p53 / MDM2 and p53 / MDM4 complex. These compounds therefore are candidate therapeutics for treating cancer as well as other cell proliferative disease states.

The invention relates to small molecules which function as inhibitors of the interaction between p53 and MDM2. The invention also relates to the use of these compounds for inhibiting cell growth, inducing cell death, inducing cell cycle arrest and / or sensitizing cells to additional agent(s).

Provided herein are peptidomimetic macrocycles containing amino acid sequences with at least two modified amino acids that form an intramolecular cross-link that can help to stabilize a secondary structure of the amino acid sequence. Suitable sequences for stabilization include those with homology to the p53 protein. These sequences can bind to the MDM2 and / or MDMX proteins. Also provided herein are methods of using such macrocycles for the treatment of diseases and disorders, such as cancers or other disorders characterized by a low level or low activity of a p53 protein or high level of activity of a MDM2 and / or MDMX protein.

Inhibitors of MDM2 and MDM2-related proteins and compositions containing the same are disclosed. Methods of using the MDM2 inhibitors in the treatment of diseases and conditions wherein inhibition of an interaction between p53 and MDM2 provides a benefit, like cancers, also are disclosed.

Provided are methods of treating lung cancer in a patient in need thereof. The method includes administration to the patient a composition comprising a therapeutically effective amount of a compound that reduces the expression level of E3 ubiquitin-protein ligase MDM2. The compound in certain instances is a miR-660 miRNA, or a functional variant thereof. The patient in need of treatment in certain instances expresses miR-660 in a lung tissue sample or biological fluid sample at a level lower as compared to a control level derived from a subject or plurality of subjects that do not have lung cancer, or as compared to a control level derived from a lung cancer patient or plurality thereof, that have been given a favorable prognosis; expresses MDM2 at a higher level in a lung tissue sample or biological fluid sample as compared to a control level derived from a subject or plurality of subjects that do not have lung cancer, or as compared to a control level derived from a lung cancer patient or plurality thereof that have been given a favorable prognosis; and / or expresses p53 in a lung tissue sample or a biological fluid sample below a control level derived from a lung tumor tissue sample, or plurality thereof, or a biological fluid sample, or plurality thereof, obtained from a patient that has a favorable lung cancer prognosis; or a control level derived from a healthy subject.

The present invention relates to the use of one or more biomarkers to evaluate the likelihood that a CDK4 inhibitor would produce an anti-cancer effect in a subject. It is based, at least in part, on the discovery that cancer treatment with a CDK4 inhibitor is more effective where treated cancer cells undergo cellular senescence rather than a transient cell cycle arrest, where cellular senescence is associated with decreased MDM2 protein level. Accordingly, in non-limiting embodiments, the present invention provides for methods, compositions, and kits for a companion diagnostic for CDK4 inhibitors, and in particular, to the use of MDM2 expression as a biomarker for the likelihood that a cancer can be successfully treated by CDK4 inhibition.

An object of the present invention is to provide a method of producing a myeloid blood cell possessing a proliferative capability. According to the present invention, provided is a method of producing a myeloid blood cell possessing a proliferative capability, including forcedly expressing (A) a cMYC gene, and (B) at least one gene selected from the group consisting of a BMI1 gene, an EZH2 gene, an MDM2 gene, an MDM4 gene, and an HIF1A gene in a myeloid blood cell.

The invention relates to the technical field of medicinal chemistry, particularly discloses a small-molecule inhibitor of Mdm<X> / Mdm<2>, and also relates to a preparation method of the small-molecule inhibitor of Mdm<X> / Mdm<2>. The small-molecule inhibitor compound can inhibit the interaction of Mdm<X> protein and p53 protein and also can inhibit the interaction of Mdm<2> protein and p53 protein, has antiproliferative activity on cancer cells, and cannot generate toxic and side effects on patients. The small-molecule inhibitor compound can be combined with other therapies for use.

The invention discloses a detection kit used for detecting the serum autoantibody of mammals. The detection kit comprises an antigen protein, wherein the antigen protein is a combination of five or more out of p53, Annexin1, CAGE, NY-ESO-1, HuD, Cyclin D, PGP9.5, GBU4-5, MDM2, GAGE7, XAGE1b, SOX2, MAGE A1 and MAGE A4. The detection kit adopts a group of novel antigen combination corresponding to the autoantibody of a biomarker related to cancers, utilizes biotins to form characteristics of a polymer to envelope the antigen protein, and uses an anti-human label peptide as a standard of quantitative detection, thus increasing the detection sensibility and accuracy of the serum autoantibody, and providing an optimized detection method for using the autoantibody to carry out cancer diagnosis.

An object of the present invention is to provide a method of producing a myeloid blood cell possessing a proliferative capability. According to the present invention, provided is a method of producing a myeloid blood cell possessing a proliferative capability, including forcedly expressing (A) a cMYC gene, and (B) at least one gene selected from the group consisting of a BMI1 gene, an EZH2 gene, an MDM2 gene, an MDM4 gene, and an HIF1A gene in a myeloid blood cell.

The present invention relates to the mechanism of ARF-mediated cell growth suppression. ARF-BP1 is identified as a novel ubiquitin ligase, and a major component of ARF-containing nuclear complexes in human cells. The present invention discloses a novel mechanism of ARF-mediated p53 activation and that ARF-BP1 is a critical mediator of both p53-independent and p53-dependent tumor suppression functions of ARF. Inactivation of ARF-BP1 in normal cells stabilizes p53 and induces p53-dependent apoptosis. Inactivation of ARF-BP1, but not Mdm2, in p53-wildtype cells promotes cell growth inhibition in a manner reminiscent of ARF induction. ARF-BP1 directly binds and ubiquitinates p53 and inactivation of endogenous ARF-BP1 is crucial for ARF-mediated p53 stabilization in Mdm2-null cells. ARF-BP1 is advantageous over Mdm2 as a target for suppressing tumor cell growth regardless of p53 status.

The invention discloses an inhibitor by virtue of interaction of P53-MDM2 and applications of the inhibitor. The inhibitor by virtue of interaction of P53-MDM2 is ganoderic acid X, ganoderic acid Me, ganoderic acid Y, ganoderic acid T or ganoderic acid F or a composition formed by combining one of ganoderic acid X, ganoderic acid Me, ganoderic acid Y, ganoderic acid T and ganoderic acid F with pharmacologically acceptable additive components. The inhibitor by virtue of interaction of P53-MDM2, disclosed by the invention, is applied to promotion of the apoptosis of tumor cells and particularly applied to promotion of the apoptosis of the 95-D lung cancer cells expressing P53 proteins or H1299 lung cancer cells not expressing the P53 proteins; the inhibitor by virtue of interaction of P53-MDM2, disclosed by the invention, has the effects of remarkably inhibiting the activity of MDM2 in human malignant lung cancer cells, thereby inhibiting the degradation of the P53 proteins and further promoting the apoptosis of the tumor cells containing P53.

A fragment-based strategy, involving “multicomponent reaction chemistry” (MCR), can identify novel chemotypes that disrupt the p53 / MDM2 or p53 / MDM4 complex employs. This approach uses high resolution structural information to delineate the region of a first protein or a ligand that is nestled within the binding pocket of a second target protein. The identified region is imported into a database containing MCR scaffolds to generate a virtual library of compounds, which subsequently are docked into the binding pocket of the target protein. Results from docking then are used to select compounds for synthesis and screening. A complementary, NMR-based methodology allows for screening the ability of compounds, selected using MCR, to disrupt the p53 / MDM2 or p53 / MDM4 complex.

The invention relates to processes for preparing isoindolin-1-one derivatives, and in particular processes for preparing (2S,3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4-chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1- (oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H-isoindol-2-yl]-2-methylpropanoic acid. The invention also relates to crystalline forms of the compound (2S,3S)-3-(4-chlorophenyl)-3-[(1R)-1-(4- chlorophenyl)-7-fluoro-5-[(1S)-1-hydroxy-1-(oxan-4-yl)propyl]-1-methoxy-3-oxo-2,3-dihydro-1H- isoindol-2-yl]-2-methylpropanoic acid and its salts.

The invention relates to compounds of formula (I):as described herein, pharmaceutical preparations comprising such compounds, uses and methods of use for such compounds in the treatment of a disorder or a disease mediated by the activity of MDM2 and / or MDM4, and combinations comprising such compounds.

The invention relates to 3-heterocyclyl indolyl compounds of formula I capable of inhibiting the interaction between p53, or variants thereof, and MDM2 and / or MDM4, or variants thereof, respectively:whereinR1, R2, R3, R4, RA, Y and Y are as defined in the specification. Due to their activity, the compounds are useful in the treatment of various disorders and diseases mediated by the activity of MDM2 and / or MDM4, or variants thereof, such as inflammatory or proliferative diseases or in the protection of cells.