110 results about "Mdm2" patented technology

A treatment method, wherein a drug containing a DNA alkylating agent prodrug compound and a salt, ester, solvate, and isotopic isomer thereof and a drug upregulating p53 protein expression or activating p53 function are used in combination for treating cancer and tumor patients. Use of the drug containing the DNA alkylating agent prodrug compound and a salt, ester, solvate, and isotopic isomer thereof in combination with the drug upregulating p53 protein expression or activating p53 function in the preparation of a drug for treating cancers and tumors. A method using the DNA alkylating agent prodrug compound and a salt, ester, solvate, and isotopic isomer thereof in combination with the drug upregulating p53 protein expression or activating p53 function in order to inhibit the growth of cells which are separated from organisms. A pharmaceutical composition containing the DNA alkylating agent prodrug compound and a salt, ester, solvate, and isotopic isomer thereof and the drug upregulating p53 protein expression or activating p53 function; the pharmaceutical composition is configured such that the drug containing the DNA alkylating agent prodrug compound and a salt, ester, solvate, and isotopic isomer thereof and a drug containing a p53-MDM2 inhibitor are used in combination for treating cancer and tumor patients.

The present invention relates to MDM2 degraders, their liquid formulations, and methods of use thereof for treating cancer.

The invention discloses a novel EGFR (epidermal growth factor receptor) degradation agent as well as a preparation method and application thereof. The EGFR degradation agent is PROTAC with GROs (such as AS1411) as an MDM2 recruitment element, target protein EGFR and E3 ubiquitin ligase MDM2 can be pulled close in vivo, so that the EGFR is labeled with ubiquitin, and then the EGFR is degraded through a ubiquitin-proteasome pathway. Experiments show that the EGFR degradation agent can effectively degrade EGFR and generate corresponding curative effects (such as inhibition of tumor cell proliferation and promotion of tumor cell apoptosis), and has very good application prospects and research values. In addition, the inventor also finds that AS1411 can specifically target and penetrate a hematoma barrier, and can be used for in-vivo imaging, diagnosis and detection of brain tumors.

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 invention discloses an anti-PCNA protein nano antibody, a fusion protein and application thereof, and belongs to the technical field of biology. According to the invention, the nano antibody specifically targeting PCNA is designed by using an artificial intelligence technology, and the nano antibody has good specificity and high affinity, and can be efficiently combined with a PCNA antigen; furthermore, rational design of the nano-antibody is carried out through artificial intelligence, so that a nano-antibody mutant with higher affinity is obtained; furthermore, a nano antibody or a nano antibody mutant with high affinity and good specificity is fused with an RBCC structural domain or a mutant thereof to obtain a fusion protein, and the fusion protein can utilize the specificity of the nano antibody structural domain to bind a target protein and start a protein degradation pathway, so that targeted degradation of the PCNA protein is realized; and p53 in the cells is activated to be phosphorylated so as to avoid ubiquitination degradation by ubiquitin ligase such as MDM2 and the like, so that the method has a very great clinical application value.

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 invention discloses an in-situ dePEGylation nano drug delivery system as well as a preparation method and application of the in-situ dePEGylation nano drug delivery system. The preparation method comprises the following steps: adding EDC.HCl and NHS into DMF (Dimethyl Formamide) containing mPEG-COOH, and stirring at room temperature; dropwise adding the activated solution into a DMF (Dimethyl Formamide) solution containing MMP2 sensitive peptide, stirring overnight at room temperature, dialyzing and freeze-drying to obtain MMP2 sensitive peptide-PEG-COOH; continuously activating terminal carboxyl, adding MDM2 targeting peptide, stirring at room temperature, dialyzing and freeze-drying to obtain a PEG-MMP2 peptide-MDM2 peptide compound; dissolving the compound in chloroform / methanol, performing ultrasonic dissolution, sequentially adding Dox and ATO nanoparticles, and stirring to form an oil phase solution; and carrying out rotary evaporation to form a film, carrying out PBS resuspension and ultrasonic hydration, and carrying out dialysis and purification to obtain the nano drug delivery system. Peeling of the PEG layer is specifically triggered through a tumor microenvironment, and precise drug release and synergistic anti-tumor treatment are realized in combination with a multi-stage response mechanism.

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.

Provided herein are methods of treating a cardiomyopathy and / or myocardial microvascular dysfunction, increasing myocardial capillary growth, reducing left ventricular hypertrophy, and / or reducing left ventricular dysfunction in a subject comprising administering an MDM2 inhibitor to the subject.

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.

To provide: 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 and intermediates; processes for making the intermediates; and crystalline forms of the compound and the intermediates.SOLUTION: The invention provides a crystalline compound of the formula in the figure, pharmaceutical compositions comprising the compound, and the like.SELECTED DRAWING: None

The disclosure relates to the in vitro use of the combined (i) measure of MDM2-encoding DNA and (ii) measure of interleukin 6 protein, in platelets, or in extracellular vesicles carried by platelets, of a subject, as a biomarker indicative of the occurrence of a cancer having chromatin-bound MDM2 in the said subject.

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 disclosure relates to pharmaceutical compositions comprising a solid dispersion comprising a compound of Formula (I): (I), or a pharmaceutically acceptable salt thereof, as well as methods of treatment.

Methods of treating myelofibrosis using a Mouse double minute 2 homolog (MDM2) inhibitor and a JAK inhibitor as a combination therapy for patients having a suboptimal response to the JAK inhibitor monotherapy.

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.

The present invention relates to single therapy comprising an effective amount of a MDM2 inhibitor, as well as combination therapies comprising an effective amount of a modulator of the immune checkpoint molecule; and an effective amount of a MDM2 inhibitor, wherein the MDM2 inhibitor is represented by the following formula or a pharmaceutically acceptable salt thereof.

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 disclosure provides a compound shown in formula (I) and a prodrug thereof, which have a good MDM2 and / or MDMX inhibiting effect and may be used for treating MDM2 and / or MDMX-mediated symptoms and / or diseases such as neoplastic diseases and / or idiopathic pulmonary fibrosis and preparing drugs for such symptoms or diseases. In particular, a compound containing a phosphoric acid (phosphate) structure has higher solubility. As the prodrug, the compound can release an MDM2 and / or MDMX double-target inhibitor compound with high activity in an animal body, which solves the problem that such double-target inhibitors are hardly prepared into drugs.

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.