84 results about "Mdm2 Protein" patented technology

There is provided a novel compound that inhibits interaction between murine double minute 2 (Mdm2) protein and p53 protein and exhibits anti-tumor activity. The present invention provides an imidazothiazole derivative represented by the following formula (1) having various substituents that inhibits interaction between Mdm2 protein and p53 protein and exhibits anti-tumor activity:wherein R1, R2, R3, R4, and R5 in the formula (1) each has the same meaning as defined in the specification.

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).

Contemplated systems and methods allow for computational genomic analysis using paired-end sequence analysis and split read refinement to thereby identify high-confidence breakpoints associated with high copy numbers and orientation of rearrangements, which is then the basis for full reconstruction of double minutes (DM). In especially preferred aspects, the DM will also include an oncogene or tumor suppressor gene, and / or may be found in blood or blood derived fluids.

The present invention is directed to a combinational therapy for treating cancer or other cell proliferative diseases. Such a therapy combines the use of radiation therapy or chemotherapy with the use of a small molecule inhibitor of the MDM2: p53 interaction.

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).

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.

Provided herein are methods for selecting and treating a subject with leukemia, wherein the subject is selected for treatment and is treated with an MDM2 inhibitor because said subject's cells contain an FLT3-ITD mutation.

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.

Provided is a method of treating a proliferative disease, condition, or disorder in a subject by administering a combination of an inhibitor of p53 and MDM2 binding and an EGFR inhibitor. Various embodiments of the disclosed methods provide a synergistic anti-proliferative or anti-apoptotic effect compared to administration of one agent alone.

The present invention is directed to a method of protecting one or more cells from programmed cytotoxic cell death by contacting the cells with a cytoprotective amount of an MDM2 and / or HDM2 inhibitor. The cytoprotective amount of inhibitor is typically used as a pulsed administration. Useful inhibitors include a class of 1,4-benzodiazepines, which act as inhibitors of MDM2-p53 interactions. The method of the invention can be employed as an adjunct to chemotherapy or radiation therapy. In addition, the methods of the invention can be employed to treat a disease or condition that involves excessive cell death.

Provided herein are compounds, compositions, and methods in the field of medicinal chemistry. The compounds and compositions provided herein relate to spiro-oxindoles which function as antagonists of the interaction between p53 and MDM2, and their use as therapeutics for the treatment of cancer and other diseases.

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).

In fibrotic lung fibroblasts, basal levels of p53 protein (and miR-34a) are markedly suppressed, leading to reduced p53-mediated inhibition of uPA and uPAR, or concurrent induction of PAI-1. These changes contribute to excessive FL-fibroblast proliferation and production of extracellular matrix (ECM), and, therefore, pulmonary fibrosis. These processes are reversed by treating the cells, and treating subjects suffering from idiopathic pulmonary fibrosis (IPF) with the small organic molecule nutlin-3a (NTL) or with a peptide, CSP-4 (SEQ ID NO:1), or variants or derivatives or multimers of this peptide, which increase p53 levels by inhibiting MDM2-mediated degradation of p53 protein. Use of these compounds serves as a new approach to the treatment of IPF, they restore p53 expression and p53-mediated changes in the uPA-fibrinolytic system in FL-fibroblasts and restrict production and deposition of ECM.

Provided herein are compounds, compositions, and methods in the field of medicinal chemistry. The compounds and compositions provided herein relate to spiro-oxindoles which function as antagonists of the interaction between p53 and MDM2, and their use as therapeutics for the treatment of cancer and other diseases.

The present disclosure relates to the field of oncology, more particularly to the field of melanoma. Provided are methods of treating melanoma, particularly advanced cutaneous melanoma, with a combination of pharmaceutical agents comprising MDM4-specific antagonists (such as an inhibitor of the MDM4-p53 interaction or a molecule that decreases MDM4 protein stability) or MDM4-MDM2 dual inhibitors (i.e., molecules that disrupt the interactions between p53 and MDM2 and p53 and MDM4) and one or more chemotherapeutic agents such as for example alkylating agents (i.e., Dacarbazine (DITC) or melphalan), alkylating-like agents (i.e., cisplatin or carboplatin) or mitotic inhibitors (taxanes docetaxel or paclitaxel) and PI3K-AKT, B-RAF and MEK inhibitors. Further provided are pharmaceutical formulations of MDM4-specific antagonists (be it an inhibitor of the MDM4-p53 interaction or a molecule that decreases MDM4 protein stability) or MDM4-MDM2 dual inhibitors (i.e., molecules that disrupt the interactions between p53 and MDM2 and p53 and MDM4) and a pharmaceutical formulation of one or more chemotherapeutic agents such as for example alkylating agents (i.e., Dacarbazine (DITC) or melphalan), alkylating-like agents (i.e., cisplatin or carboplatin) or mitotic inhibitors (taxanes docetaxel or paclitaxel) and B-RAF and MEK inhibitors.

Provided herein are compounds, compositions, and methods in the field of medicinal chemistry. The compounds and compositions provided herein relate to spiro-oxindoles which function as antagonists of the interaction between p53 and MDM2, and their use as therapeutics for the treatment of cancer and other diseases.

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).

This invention is based in part on the discovery that miR-34 is independent of p53. It has been discovered that miR-34 functions in a TP53 -independent tumor suppression pathway. Specifically, miR-34-induced inhibition of cancer cell growth was found to be the same in p53-normal and p53-deficient cells. Thus, miR-34 has a more central role during tumor suppression that is uncoupled from p53. In the absence of p53, miR-34, unlike certain other miRNAs, is sufficient to induce an up-regulation of genes known to be regulated by p53, including but not limited to p21<CIP1 / WAF1>(CDKN1A), PUMA, BAX, NOXA, PHLDA3, and MDM2 and a down-regulation of HDAC1. Therefore, these biomarkers can be used as biomarkers of miR-34 activity. The invention is further based on the discovery that some of these biomarkers are indispensable for a therapeutic response to miR-34 activity, and are thus prerequisite biomarkers of miR-34 activity.

There is provided compounds that inhibit interaction between murine double minute 2 (Mdm2) protein and p53 protein and exhibits anti-tumor activity. Compounds include imidazothiazole derivatives that can inhibit interaction between Mdm2 protein and p53 protein and exhibits anti-tumor activity.

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 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.

Use of at least an MDM2 gene panel, preferably a four gene MDM2 gene panel, as a biomarker for predicting the response to a MDM2 antagonist.

The invention discloses an MDM2 gene which is a novel predisposing gene of nasopharyngeal darcinoma by relating the SNP 309 polymorphic loci of the MDM2 gene with the risk of the nasopharyngeal darcinoma and the more serious lymph node metastasis, thereby providing new genetic counseling contents and the molecule criterion for people to prevent and control the nasopharyngeal darcinoma. In addition, the invention also relates to a method for detecting the SNP309 polymorphic loci and the corresponding detecting kit, wherein, the detecting method is the PCR product direct sequencing method that is the polymerase chain reaction-sequencing method.