76 results about "Mdm2" patented technology

The invention belongs to the technical field of biology, and particularly relates to a fusion protein and application thereof in competitive inhibition of MDM2 and further recovery of TP53 activity. The fusion protein provided by the invention comprises an antibody fragment, a modified progesterone receptor and an RING subunit of an antibody receptor Trim21 which are connected in sequence, has a composite structure of an antibody and a part of subunits of the Trim21, can specifically degrade a target protein, competitively inhibits MDM2 while degrading the target protein, further recovers the activity of a P53 gene, and has a good application prospect. The anti-tumor effect is also realized.

The present invention discloses a small molecule compound having a substituted phenylspiro[indoline-3,3'-pyrrolidine] structure, the structure of which is shown in General Formula I, and the definitions of each substituent as described in the specification and claims. The compound of the present invention can inhibit the protein-protein interactions of MDM2-p53 and MDMX-p53 proteins. As a small molecule inhibitor of the protein-protein interactions of MDM2-p53 and MDMX-p53 proteins, it is used in the preparation of a drug for preventing and / or treating diseases related to MDM2 and MDMX, particularly tumors.

The present invention provides processes for making 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 and processes for making the intermediates. Also provided are crystalline forms of the compound and the intermediates.

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 provides a MDM2 inhibitor, a preparation method, a pharmaceutical composition and an application thereof. Specifically, the present application provides a compound as shown in formula I, wherein the definitions of each group are described in the description. The compound has excellent MDM2 inhibitory activity, and thus can be used for preparing a pharmaceutical composition for treating cancer (particularly, p53 wild-type cancer) and other diseases related to MDM2 activity.

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 disclosure generally relates to cancer therapies and, in some embodiments, to using genetic circuits designed for targeted cancer therapies. The genetic circuit, in some embodiments, utilizes a suitable vector capable of delivering DNA sequences comprising functional units comprising a transcriptional promoter, target sequences and a transcriptional terminator. Together, the genetic circuit, in some embodiments, may trigger apoptosis — a target protein activity where cell death occurs — in cancer cells, and protect non-cancer cells from apoptosis. In some embodiments, the genetic circuit may direct target protein activity in cancer cells, while not directing protein activity in non-cancer cells. However, in the presence of certain stimuli, the inhibition is relieved, which may lead to the induction of target protein activity in cancer cells. In addition, some embodiments are generally directed to vectors comprising a first sequence encoding at least a portion of Mdm2 and a promoter, and a second sequence encoding a promoter and a fusion protein comprising at least a portion of p53 and iCasp-9 (or another protein capable of achieving a therapeutic objective), optionally connected by a linker sequence capable of allowing each protein subunit of the fusion protein to be independently active but subject to the same proteolytic pathways as p53 in cancer and non-cancer cells. Other aspects are generally directed to methods of making or using such compositions, kits including such compositions, or the like.

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.

Provided is use of an MDM2 inhibitor in weight management by inducing weight loss in a subject, as well as the MDM2 inhibitor in the treatment and / or prevention of obesity, dyslipidemia, a non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and / or type 2 diabetes. The present invention further relates to a method for using the MDM2 inhibitor in the use.

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 invention relates to a compound of formula (I) wherein R1 represents a halogen atom, a (C1-C6) alkyl group, a (C3-C6) cycloalkyl group, a (C2-C6) alkenyl group, a (C1-C6) alkoxy group or a (C3-C6) cycloalkyloxy group, X and Y independently represent a-CH = group,-CR3 = group or-N = group, Z1 and Z2 independently represent a-CH2-group, an = CH-group or an = N-group, and R3 and R4 independently represent a hydrogen atom or a halogen atom, or any pharmaceutically acceptable salt thereof. The invention also relates to the use of the compounds as a medicament, in particular for the treatment and / or prevention of cancers, in particular cancers exhibiting recruitment of MDM2 to chromatin, the present invention relates to a cancer, more particularly a cancer selected from the group consisting of bone cancer, brain cancer, ovarian cancer, breast cancer, lung cancer, colorectal cancer, osteosarcoma, skin cancer, leukemia (including acute myelogenous leukemia), pancreatic cancer, prostate cancer and liposarcoma, even more particularly a cancer selected from the group consisting of skin cancer, liposarcoma and leukemia, such as but not limited to liposarcoma, melanoma and acute myelogenous leukemia.

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.

To provide a process for preparing MDM2 inhibitors useful for treating solid tumors such as breast, colon, lung, and prostate tumors, as well as liquid tumors such as lymphomas and leukemias.SOLUTION: Provided are 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 and intermediates thereof.SELECTED DRAWING: Figure 1

The invention provides application of bufalin based on an MDM2-GPX4 regulatory pathway in preparation of non-small cell lung cancer resisting drugs, and relates to the technical field of biological medicines. According to the application, the medicine induces non-small cell lung cancer cells to generate ferroptosis through an MDM2-GPX4 regulatory pathway, so that occurrence and development of the non-small cell lung cancer are inhibited, the non-small cell lung cancer is p53 mutant non-small cell lung cancer, bufalin is directly combined with MDM2 to play a role of molecular glue, MDM2 and GPX4 are promoted to form an interaction compound, and the non-small cell lung cancer can be effectively inhibited. Further, GPX4 function inhibition or degradation is mediated, and ferroptosis is induced. The GPX4 is regulated through the E3 ubiquitin ligase function of the MDM2 for the first time, p53 mutant NSCLC can be effectively treated without relying on p53 activity, the problem that the application range of a traditional MDM2 inhibitor is limited is solved, the mechanism is clear, a bufalin (drug)-MDM2 / GPX4 (target)-ferroptosis (pathway) three-level regulation network is illuminated, and the uncertainty and risk of clinical development are reduced.

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 an antisense oligonucleotide medicine for treating pituitary tumor. According to evidence of molecular biology experiments and the like and verification in human primary pituitary tumor cells, the designed specific ASO medicine is applied to treatment of pituitary tumors for the first time. The ASO drug inhibits the expression of MDM2, recovers the activity of P53 protein, inhibits the proliferation of pituitary tumors and promotes apoptosis by inhibiting the splicing process mediated by a splicing factor FUS, and provides a new direction for a potential medication scheme for pituitary tumor treatment.

The invention belongs to the technical field of biological medicines, and relates to application of small nucleolus SnoRD89 in preparation of an ovarian cancer targeting drug. The invention discloses that SnoRD89 inhibits the malignant phenotype of ovarian cancer cells by influencing the RPL11 / MDM2 / P53 pathway for the first time. The invention finds a new effective method for targeted regulation and control of apoptosis signal channels, that is, ovarian cancer cell apoptosis is induced through siRNA of targeted SnoRD89, and the method is applied to basic medical research.

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.