41 results about "Mdm2" patented technology

The present invention relates to a method of determining the responsiveness of a cancer patient to treatment with a compound that inhibits a KRAS protein or a KRAS protein mutant or treatment with a compound that inhibits the interaction between MDM2 and p53, the method comprising measuring the survivin level in a first sample obtained from the patient prior to treatment with the compound, measuring the level of survivin in a second sample obtained from the patient during or after treatment with the compound, comparing the level of survivin in the second sample to the level of survivin in the first sample, and determining the level of survivin in the second sample when compared to the level of survivin in the first sample. When the survivin level in the second sample decreases, it is determined that the patient is responsive to treatment with the compound. The invention further relates to the use of survivin in compounds for determining the inhibition of KRAS protein or KRAS protein mutants, or in compounds for inhibiting the interaction between MDM2 and p53, or a pharmaceutical formulation comprising said compound that inhibits a KRAS protein or a KRAS protein mutant or said compound that inhibits an interaction between MDM2 and p53 in a method of treating cancer.

The invention discloses a recombinant deubiquitination enzyme USP7 mutant, a preparation method and application of the mutant in tumor treatment, and belongs to the technical field of biomedicine.The USP7 mutant changes substrate selectivity through site-specific mutagenesis, specifically deubiquitination tumor suppression protein p53 is achieved, meanwhile, oncogenic protein MDM2 is unstable, a p53 anti-tumor pathway is activated, and the tumor suppression protein p53 is activated. The mutant induces cell cycle arrest and apoptosis in wild type p53 tumor cells, the ICvalue is 180-280nM, animal experiments show that the tumor growth inhibition rate reaches 72%, the tumor tissue enrichment is improved by 12 times by combining a folic acid targeted lipid nanoparticle delivery system, the drug resistance of an MDM2 inhibitor is overcome, the mutant has a synergistic effect with chemotherapeutic drugs, and the mutant can be used for preparing drugs for treating tumors. And a novel accurate treatment strategy is provided for wild-type p53 tumors.

The present application relates to a kind of triplex-forming oligonucleotides (TFOs) sequence and its pharmaceutical application, especially to a kind of triplex-forming oligonucleotides sequence and its pharmaceutical application for inhibiting MDM2 and MDM4 gene amplification.The triplex-forming oligonucleotides sequence provided by the present application can form triplex structure locally in the amplified MDM2 / MDM4 gene of tumor cell, cause its replication stress, finally lead to the apoptosis of tumor cell.The triplex-forming oligonucleotides sequence provided by the present application and the medicine prepared using the sequence are aimed at the MDM2 / MDM4 amplification gene sequence of tumor rather than protein, have good drug resistance, and have no effect on normal cell without MDM2 / MDM4 gene amplification, have excellent safety, thus have good therapeutic effect on the tumor with MDM2 / MDM4 gene amplification.

The present invention relates to compounds and methods useful for the modulation of mouse double minute 2 homolog (“MDM2”) protein via ubiquitination and / or degradation by compounds according to the present invention.

Disclosed are a protein degrader targeting O-GlcNAc Transferase (OGT), and a preparation method therefor and a use thereof. The inventors of the present invention have creatively discovered that a compound recruits MDM2 by means of its interaction with nucleolin (NCL), and through further experiments have found that it can serve as a novel recruiting element for MDM2, which can be used in the preparation of targeted protein degraders and other applications. Using the above findings, the inventors have prepared a novel protein degrader compound targeting OGT, and have found through experimentation that the prepared targeted protein degrader can effectively induce the degradation of OGT, for use in the treatment of diseases mediated by OGT or associated with O-GlcNAc glycosylation (such as neurodegenerative diseases, obesity, tumors, diabetes and complications thereof, cardiovascular diseases, etc.), and will have very promising application prospects in the fields of medicine and health management.

The application discloses application of a petroleum ether extract of a root of a roadside green plant in preparation of a drug for treating colorectal cancer by regulating a PI3K / AKT / MDM2 / p53 pathway. In the application, the petroleum ether extract of the root of the roadside green plant for treating colorectal cancer is obtained by petroleum ether reflux extraction of the root of the roadside green plant. Pharmacological experiments show that the petroleum ether extract of the root of the roadside green plant treats colorectal cancer by regulating the PI3K / AKT / MDM2 / p53 signal pathway through down-regulating p-PI3K / PI3K and p-AKT / AKT ratio, up-regulating p-MDM2 and down-regulating p53 level; the extract has an anti-malignant proliferation effect, induces G1 phase arrest by targeting CDK2, up-regulating p21, down-regulating Cyclin E1-CDK2 and Cyclin D1-CDK4; the extract induces HCT-116 cell apoptosis through a mitochondrial pathway by up-regulating Bax / Bcl-2, reducing ΔΨm, releasing Cyt C, activating Caspase-9 / 3 and cleaving PARP; the extract inhibits migration and invasion of HCT-116 cells by targeting MMP9, down-regulating MMP-2, MMP-9 and N-cadherin expression and up-regulating E-cadherin expression. In addition, the extract inhibits growth of a transplanted tumor in a nude mouse transplanted tumor model by inducing apoptosis of transplanted tumor cells.

Mutations in oncogenes and tumor suppressors contribute to the development and progression of cancer. The present disclosure describes methods of recovering wild-type function to p53 mutants by treating a tumor with a compound and a second agent. The compounds of the present invention can bind to mutant p53 and restore the ability of the p53 mutant to bind DNA and activate downstream effectors involved in tumor suppression. The disclosed compounds can be used in combination with an MDM2, PI3K, or AKT inhibitor to reduce the progression of cancers that contain a p53 mutation.

The description relates to MDM2 binding compounds, including bifunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and / or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the description provides compounds, which contain on one end a ligand which binds to the MDM2 E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation / inhibition of targeted polypeptides of nearly any type.

The present invention relates to compounds useful for selective inhibition of MDM2 amplification cancer and pharmaceutical compositions thereof.

Provided are biomarkers for predicting the efficacy of an MDM2 inhibitor or a Bcl-2 / Bcl-xL dual inhibitor or a Bcl-2 inhibitor or a Bcl-xL inhibitor in treating a cancer patient. Also provided are compositions, e.g., kits, for assessing gene levels of the biomarkers, and methods of using such gene levels to predict the response of a cancer patient to an MDM2 inhibitor or a Bcl-2 / Bcl-xL dual inhibitor or a Bcl-2 inhibitor or a Bcl-xL inhibitor. Such information can be used to determine the prognosis and treatment selection of a cancer patient.

The present application provides 2-indolinone spiroketone compounds or salts, amorphous forms or crystalline forms thereof as MDM2 inhibitors, and preparation methods and applications thereof. The amorphous forms or crystalline forms of the present application have good stability, and have very important values for drug development, preparation development and production.

Pharmaceutical compositions and compounds comprising a phosphorothioated CpG oligodeoxynucleotide linked to a DNA oligonucleotide that is hybridized an RNA aptamer are useful in methods of treating cancer (such as leukemia) and methods of inhibiting DNA methyltransferase. In embodiments, the RNA aptamer binds to an intracellular target such as DNMT1, NF-kB, RUNX1, MYC, MYB, ETS, PAX5, MDM2, F0XM1, PU.l, STAT3, STATS. STAT6, FAD, ATP5B, or beta-catenin.

Disclosed herein are compounds that may be used to degrade mdm2 that contain one or more rigid linkers in the connection between the mdm2 targeting compound and the degrader. These compound may show improved activity in reducing the mdm2 levels. These compound may be used to treating a disease or disorder such as cancer.

The invention discloses a protein degradation agent targeting IRAK4 as well as a preparation method and application of the protein degradation agent. The inventor of the invention creatively discovers that a compound recruits ubiquitin ligase MDM2 through interaction with NCL, and further experiments discover that the compound can be used as a novel recruitment element of MDM2 and is used in the aspects of preparation of a targeted protein degradation agent and the like. The inventor prepares a novel degradation agent compound targeting IRAK4 by utilizing the discovery, and experiments find that the prepared compound can effectively induce degradation of IRAK4, is used for treating IRAK4-mediated diseases (such as inflammatory diseases), and has a very good application prospect in the field of medicines.

The invention discloses a TYK2-targeted protein degradation agent as well as a preparation method and application thereof. The inventor creatively discovers that the compound recruits E3 ubiquitin ligase MDM2 through interaction with NCL, and further experiments discover that the compound can be used as a novel recruitment element of the MDM2 to be used in the aspects of preparation of a targeted protein degradation agent and the like. The inventor prepares a novel TYK2-targeting protein degradation agent compound by utilizing the discovery, and experiments find that the prepared TYK2-targeting protein degradation agent can effectively induce degradation of TYK2, is used for treating TYK2-mediated diseases (such as autoimmune diseases and inflammatory diseases), and has a very good application prospect in the field of medicines.

The invention discloses a protein degradation agent targeting GSK-3 as well as a preparation method and application of the protein degradation agent. The inventor of the invention creatively discovers that a compound recruits ubiquitin ligase MDM2 through interaction with NCL, and further experiments discover that the compound can be used as a novel recruitment element of MDM2 and is used in the aspects of preparation of a targeted protein degradation agent and the like. The inventor prepares a novel degradation agent compound targeting GSK-3 (especially GSK-3 beta) by utilizing the discovery, and experiments find that the prepared compound can effectively induce GSK-3 degradation, is used for treating GSK-3 mediated diseases (such as tumors), and has a very good application prospect in the field of medicines. In addition, the inventor also finds that the compound can penetrate through the blood brain barrier of a patient with nervous system diseases, and can be used for in-vivo imaging, diagnosis, treatment and research of nervous system diseases.

The invention discloses a protein degradation agent of targeted CRBN as well as a preparation method and application of the protein degradation agent. The inventor of the invention creatively discovers that a compound recruits ubiquitin ligase MDM2 through interaction with NCL, and further experiments discover that the compound can be used as a novel recruitment element of MDM2 and is used in the aspects of preparation of a targeted protein degradation agent and the like. The inventor prepares a novel degradation agent compound targeting CRBN by utilizing the discovery, and the experiment finds that the prepared compound can effectively induce the degradation of CRBN, is used for treating CRBN-mediated diseases (such as tumors), and has a very good application prospect in the field of medicines.

Provided are methods of targeting patient-specific oncogenes in extrachromosomal DNA (ecDNA) to treat glioma in a human. The present methods include identifying a drug that targets against an oncogene present in ecDNA of a human suffering from glioma, such as glioblastoma. The identified oncogenes present in ecDNA include MET, MET / CAPZA2, MDM2, CDK4, SOX2, PIK3CA, MECOM, PDGFRA, EGFR, MYCN, MYC, TERT, SMARCA4, RP56, FBXW7, CDK6, CCND2, ERBB2, BRCA1, and BAP1. The present methods include identifying a drug targeted against the ecDNA oncogene, which drug inhibits the function of the identified oncogene, so as to inhibit tumor growth or progression of the glioma in the human. Also provided are PDX mouse models to further identify and / or confirm patient-specific drugs that target the identified oncogene(s) present in ecDNA. Also provided are methods of diagnosing gliomas or recurrent gliomas and methods of screening or monitoring for recurrence of gliomas. Further provided are methods of validating a predicted presence of ecDNA in a brain tumor using fluorescence in situ hybridization (FISH). Also provided are methods of screening drug candidates for a patient by implanting different identified drugs that target an identified oncogene into PDX mouse models.

This invention discloses a method for targeting KRAS G12D This invention discloses a protein degrading agent, its preparation method, and its application. In this invention, the protein degrading agent uses a compound of formula I as an MDM2 recruitment element, which can bring the target protein and E3 ubiquitin ligase closer together in vivo, thereby tagging the target protein with ubiquitin and then degrading it via the ubiquitin-proteasome pathway. Experiments show that the degrading agent can effectively degrade the target protein KRAS. G12D It produces corresponding therapeutic effects, such as inhibiting the proliferation of tumor cells and promoting tumor cell apoptosis, and has very good research and application value.

According to the treatment method, a drug containing a DNA alkylating agent prodrug compound and salts, esters, solvates and isotope isomers of the DNA alkylating agent prodrug compound is combined with a drug for up-regulating p53 protein expression or activating p53 functions to treat cancer and tumor patients. The DNA alkylating agent prodrug compound, a drug of salt, ester, solvate and isotope isomer of the DNA alkylating agent prodrug compound and a drug for up-regulating p53 protein expression or activating a p53 function are combined to be applied to preparation of drugs for treating cancers and tumors. Methods for inhibiting the growth of cells detached from organisms using DNA alkylating agent prodrug compounds and salts, esters, solvates, isotopic isomers thereof in combination with drugs that up-regulate p53 protein expression or activate p53 function. The invention relates to a pharmaceutical composition containing a DNA alkylating agent prodrug compound, a salt, an ester, a solvate and an isotope isomer of the DNA alkylating agent prodrug compound, and a drug for up-regulating p53 protein expression or activating a p53 function. The drug containing the DNA alkylating agent prodrug compound and salts, esters, solvates and isotope isomers of the DNA alkylating agent prodrug compound is combined with a drug containing a p53-MDM2 inhibitor to treat cancer and tumor patients.

The invention relates to compounds according to formula (I)and pharmaceutically acceptable derivatives thereof for use as novel inhibitors of Mouse Double Minute 2 (MDM2) activity by inhibiting interactions between MDM2 and its natural negative regulator, p53. Pharmaceutical compositions containing a compound of Formula (I), or a derivative thereof, including compositions that also contain one or more additional antiproliferative agents, can be used in methods of treating proliferative diseases, including various cancers.

The invention provides a compound of formula (I): (I) or a tautomer, an episolvate or a salt thereof wherein the various substituents are as defined in the claims. Also provided are pharmaceutical compositions containing the compounds of formula (I), processes for the preparation of the compounds and the medical uses of the compounds.

The disclosure includes compounds of Formula (I), wherein each of Z, R0, R1, R2, R3, R4, R5, R6, R, L1, L2, L3, L4, L5, L6, Q1, Q2, W, m, n, r, and s, are defined herein. Also disclosed is a method for treating a neoplastic disease, autoimmune disease, and inflammatory disorder with these compounds.

The present invention provides commercial processes for preparing 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid as well as intermediates thereof.