203 results about "De ubiquitination" patented technology

According to the GPX4 protein degradation agent and the application, the degradation agent serves as molecular glue to induce tumor cell ferroptosis and is different from an existing PROTAC technology, and the molecular glue can induce interaction between E3 ubiquitin ligase and target protein GPX4 and promote ubiquitination of the E3 ubiquitin ligase and the target protein GPX4. Compared with the existing GPX4 degradation agent, the molecular glue has the advantages of small molecular weight, high cell permeability and better druggability. The GPX4 molecular glue disclosed by the invention can be used for effectively degrading GPX4 and has a killing effect on various tumor cell lines. The preparation method is simple in synthesis route and mild in reaction condition, can be used for being developed into a new generation of GPX4 targeting drugs, and has great clinical application value and considerable market potential.

The invention discloses a polypeptide-based PROTAC condensation body as well as a preparation method and application of the polypeptide-based PROTAC condensation body. The polypeptide-based PROTAC aggregate comprises an HER2 (human epidermal growth factor receptor) targeting module, an EGFR (epidermal growth factor receptor) targeting module, a VHL E3 ligase targeting module and a self-assembly module. The polypeptide-based PROTAC condensation body can dynamically enrich E3 ligase VHL and promote efficient ubiquitination degradation of HER2, EGFR and downstream signal channel protein of HER2 and EGFR, the degradation efficiency of HER2 and EGFR protein can reach 92%, the degradation efficiency of downstream signal channel protein such as SOS2 and RAS can reach 80%, and in addition, the polypeptide-based PROTAC condensation body has the advantages that the polypeptide-based PROTAC condensation body can be used as an efficient ubiquitination condensation body; the polypeptide-based PROTAC condensation body has the characteristics of tumor targeting and long-acting retention, and dose-dependent tumor specific accumulation and retention can be realized through in-situ self-assembly.

The invention relates to the technical field of biological medicine, in particular to an mRNA vaccine based on a protein degradation technology. The mRNA vaccine comprises an mRNA system and a lipid nanoparticle. The mRNA system refers to two mRNAs which can respectively encode an antigen-docking module and a recognition module-E3 ubiquitin ligase binding domain, the E3 ubiquitin ligase binding domain recruits an E3 ubiquitin ligase complex, the antigen is ubiquitinated and degraded into a peptide fragment by utilizing specific binding between the recognition module and the docking module, the peptide fragment is recognized by an MHC-I complex, and the E3 ubiquitin ligase binding domain is used for identifying the MHC-I complex. Then, the body immunity is activated, and the anti-tumor effect is realized. Besides, the invention provides a universal mRNA vaccine, that is, theoretically, different diseases can be treated only by replacing antigens in an mRNA system, the research and development time of the vaccine is greatly shortened, the research and development cost is reduced, a new thought is provided for tumor treatment, and the mRNA vaccine has a huge application prospect.

The invention discloses a PROTAC chimera for targeted degradation of an ROR [gamma] t receptor and application of the PROTAC chimera, the structure of the chimera is RW-L-Re, Re is a ligand capable of being combined with E3 ubiquitin ligase, L is a linking group covalently combined with at least one Re and at least one RW, and Rw is a target protein ROR [gamma] t binding ligand and is selected from one of the following structures. A series of PROTAC chimeras capable of degrading an ROR gamma t receptor in a targeted manner are designed and synthesized for the first time, a ternary complex is formed mainly by combining a target protein ligand and an E3 ubiquitin ligase ligand with POI and E3 ligase respectively, and then the POI is labeled with a ubiquitination tag and is further degraded by proteasome. Experimental results prove that the PROTAC chimera designed by the invention has excellent ROR [gamma] t receptor degradation activity, and can be used for preparing related drugs for treating autoimmune diseases or tumors.

The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same for the modulation of one or more SWI / SNF-related matrix associated actin dependent regulator of chromatin subfamily A (SMARCA) and / or polybromo-1 (PB-1) protein via ubiquitination and / or degradation by compounds. The compounds are bifunctional molecules that link a cereblon-binding moiety to a ligand that binds SMARCA and / or PB1 proteins.

The application discloses a PROTAC compound with RORgamma t receptor targeted degradation and purposes thereof, which is a compound with a structure shown in a general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition thereof. e is a ligand capable of combining with an E3 ubiquitin ligase; the L is a linking group covalently combining at least one R e and at least one R W ; the R w is a target protein RORgamma t binding ligand; the application is based on the target point of RORgamma t and the PROTAC technology, and a series of RORgamma t-PROTACs are designed and synthesized for the first time. The mechanism is that the target protein ligand and the E3 ubiquitin ligase ligand are combined with POI and E3 ligase respectively, so as to form a ternary complex of "POI-PROTAC-E3 ligase". Then, the POI is marked with a ubiquitination label, and is degraded by a proteasome. The advantages of RORgamma t-PROTACs mainly include targeting of "undruggable proteins", small dosage, low toxicity, and difficulty in drug resistance. W -L-R e (I)

The application relates to the field of medicinal chemistry and provides a use of a diphenylacetonitrile compound and a protein-targeting hydrolytic chimeric compound. The application finds that a diphenylacetonitrile compound shown in formula (I) directly interacts with FEM1B, thereby serving as an inhibitor of a human E3 ubiquitin ligase substrate recognition receptor FEM1B. The application also provides a compound shown in formula (II), and the compound shown in formula (II) is a protein-targeting hydrolytic chimeric (PROTAC) drug, wherein Q2 is a target protein ligand molecule, Q1 is a FEM1B inhibitor, Q2 is combined with a target protein, thereby inducing E3 ligase FEM1B combined with Q1 to approach the target protein, leading to ubiquitination and degradation of the target protein. Experimental results show that the PROTAC drug shown in formula (II) provided by the application can specifically degrade a target protein in cells. Formula (I); formula (II).

The present disclosure is concerned with compounds and compositions for use in the prevention and treatment of cancer associated with FBOX21 mediated p85a ubiquitination such as, for example, cancer (e.g., sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma)). This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

This invention discloses an enhanced CAR-T cell (CARTAC) capable of secreting a targeted membrane protein degrader and its applications. While retaining specific killing function, this cell can expand locally in tumors and continuously secrete the bispecific adaptor molecule scTAC. scTAC can recruit E3 ubiquitin ligases, mediate ubiquitination of tumor cell surface membrane proteins (such as PD-L1), and achieve targeted degradation via the lysosomal pathway, effectively reversing the immunosuppressive microenvironment, overcoming antigen heterogeneity, and eliminating antigen-negative tumor cells through the bystander effect. This invention also utilizes the efficient endocytosis properties of EGFR to design scTAC-dual, which can further enhance degradation efficiency. In various lung cancer mouse models, CARTAC-dual exhibited excellent tumor infiltration capacity, low exhaustion levels, and sustained antitumor activity, without systemic toxicity. This invention integrates the targeted killing and protein degradation delivery functions of CAR-T cells, not only enhancing the control effect on solid tumors but also possessing target scalability, making it suitable for the universal upgrading of various CAR-T products.

The present disclosure relates to novel compounds that act as modulators of cereblon (CRBN). The compounds promote CRBN-mediated ubiquitination and proteasomal degradation of oncogenic proteins such as GSPT1 and MYC, thereby suppressing abnormal cell growth. Pharmaceutical compositions containing the compounds and methods of using the compositions for the treatment of cancers, particularly solid tumors, are also provided.

The invention provides an application of hederagenin in preparation of a medicine used as an SKP2 degradation agent, and particularly provides an application of hederagenin in preparation of a medicine used as an SKP2 degradation agent. The invention also provides a PROTAC compound, which comprises a target protein POI ligand, an E3 ubiquitin ligase ligand and a linking chain Linker, the general formula of the ligand-Linker-E3 ligase ligand is as follows: a POI ligand-Linker-E3 ligase ligand. The invention also provides a preparation method and application of the PROTAC compound. The PROTAC design based on HED improves the tumor tissue targeting property, and shows low toxicity in an in-vivo experiment. The invention provides a novel SKP2 (SKP2) degradation agent. The degradation agent is expected to be capable of efficiently inducing ubiquitination degradation of SKP2 protein, and a treatment strategy with higher potential and clinical application prospect is provided for overcoming the limitation of the prior art by enhancing the specific killing capability on SKP2 high-expression tumor cells and verifying the remarkable tumor inhibition effect and good safety of the degradation agent in an animal model.

The invention discloses an engineered protein and application thereof in mediating non-ubiquitination degradation, and belongs to the technical field of biological medicine. The structural domains CATCH1 and CATCH2 of the MIDN protein and the region between the structural domains CATCH1 and CATCH2 are modified for the first time, the modification mode comprises the steps that the structural domains CATCH1 and CATCH2 and the region between the structural domains CATCH1 and CATCH2 are replaced with antibodies or polypeptides, then structure or sequence optimization is conducted on the basis, and the obtained MIDN engineered protein not only retains the proteasome binding capacity of MIDN, but also has the advantages of being capable of improving the protein quality and the like. According to the present invention, the MIDN-based target protein degradation system has the MIDN-based target protein degradation system, can expand the target range to the membrane protein or the cytoplasm protein, can improve the degradation efficiency of the MIDN-based target protein degradation system, further has the antibody-mediated target protein specificity so as to achieve the pathological / physiological protein distinguishing effect, and does not have the obvious toxicity; therefore, the engineered protein provided by the invention has a good application prospect.

The invention discloses an mBioPROTAC coding vector based on an anti-ubiquitination mutant VTA1-SPOP fusion protein and an application of the mBioPROTAC coding vector. The mBioPROTAC coding vector is formed by connecting an E3 ubiquitination ligase ligand and a target protein ligand II or a target protein ligand III by utilizing a GS linker 2. According to the invention, multi-target synergistic degradation can be realized: the VTA1 ligand (MIT1-MIT2-VSL structural domain) is simultaneously combined with ESCRT related proteins in a targeted manner, so that the mBioPROTAC coding vector can synchronously induce ubiquitination degradation of a plurality of ESCRT key components, and the limitation that the traditional PROTAC only can be degraded in a single target is overcome; the proliferation and survival of tumor cells are inhibited, the killing efficiency of cytotoxic T lymphocytes on the tumor cells is improved, and autophagosome closing and blocking are realized; the biological safety can be improved; the industrial production cost can be reduced.

The invention relates to the field of biotechnology and medicine, and discloses a polypeptide targeting molecular chaperonin TRIC / CCT and application thereof. The sequence of the polypeptide is consistent with or truncated from the C-terminal sequence of a CCT subunit, and the polypeptide can be competitively combined with CRL4-DCAF12 ubiquitin ligase, so that the ubiquitination of the CCT subunit is reduced, and the formation of a TRIC / CCT compound is inhibited; the polypeptide inhibits the formation of a TRIC / CCT compound and blocks the activation of key metastasis promoting signal channels such as YAP, STAT3 and mTOR, thereby inhibiting the metastasis of lung cancer. According to systematic in-vivo and in-vitro experiments, the compound has excellent performance in the aspect of inhibiting lung cancer cell migration and metastasis, has the characteristics of clear target spot, clear action mechanism and the like, and provides a new treatment strategy for developing a new generation of lung cancer metastasis resisting medicines.

The present application relates to a PROTAC construction based on E3 ubiquitin ligase ZER1 and target protein DVL2 and its application in heart failure treatment. In particular, the present application provides a proteolysis targeting chimera (PROTAC) complex comprising an E3 ubiquitin ligase binding ligand moiety and a target protein binding ligand moiety connected by a linker, wherein the E3 ubiquitin ligase binding ligand is a ZER1 binding ligand, and the target protein binding ligand is a DVL2 binding ligand. The PROTAC molecule in the present application targets DVL2 ubiquitination degradation by recruiting E3 ubiquitin ligase ZER1 to regulate the CaMKII / HDAC4 / MEF2C signaling axis, thereby reducing pathological cardiac hypertrophy and intervening the progression of heart failure, and providing a new therapeutic target for treating cardiac hypertrophy and heart failure caused by pressure overload.

The application discloses a method for preparing rice with changed tiller number, and belongs to the technical field of genetic breeding. The method comprises the following steps: introducing a coding gene of an OsD14 mutant into target rice to obtain rice with changed tiller number, wherein the tiller number of the rice with changed tiller number is higher or lower than that of the target rice, and the OsD14 mutant is a protein obtained by mutating the 10th, 11th, 13th and 15th amino acids in SEQ ID NO: 1 into other amino acids and keeping other amino acids in SEQ ID NO: 1 unchanged. It is proved by experiments that whether ubiquitination degradation of the OsD14 occurs is related to a phosphorylation state of the OsD14, the number of rice tillers is adjusted by using the phosphorylation state of the OsD14, and the plant type is improved, so that the yield of the rice is improved, and the method has a wide application prospect.

This invention relates to the field of pharmaceutical technology, specifically the application of NEDD8 activator in the preparation of drugs for treating Japanese encephalitis. Using human neuroblastoma cells (SH-SY5Y) as target cells, this invention utilizes activators from a library of ubiquitinated compounds to target and activate key enzymes in the ubiquitination pathway, aiming to identify host factors associated with Japanese encephalitis virus (JEV) infection of SH-SY5Y cells. This helps to understand the mechanism by which JEV invades the central nervous system and causes neuronal cell damage, and also provides new targets for therapeutic drugs against JEV-induced Japanese encephalitis. This invention experimentally discovered that NEDD8 activator (NAE) has the property of inhibiting JEV infection of SH-SY5Y cells. This invention provides the application of NEDD8 activator in the preparation of drugs for treating Japanese encephalitis, offering new targets and treatment strategies for the prevention and treatment of JEV.

The present invention relates to a complex comprising i) a catalytically inactive site-specific nuclease linked to ii) an array of between two and ten, preferably three to seven effector domains each having a specific chromatin modifying activity, such as, for example, a specific DNA methylation activity, a histone methylation activity, a specific histone acetylation or ubiquitination activity, and / or a specific chromatin demethylation / deacetylation activity, wherein the effector domains are each separated by a linker providing sufficient distance between the domains and the nuclease in order not to substantially interfere with their specific chromatin modifying activities, and the binding of the site-specific nuclease, as well as respective methods involving the complex and use of the complex.

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 invention discloses a compound for targeted ubiquitination degradation of USP7 protein, and a medicinal composition and application thereof. The structural formula of the E3 ubiquitin ligase complex is as shown in formula I. A is a specific protein ligand in the E3 ubiquitin ligase complex; l is a bivalent linking group between a USP7 protein small molecule ligand and a specific protein ligand in an E3 ubiquitin ligase complex. The protein degradation chimera has the activity of inhibiting USP7 protein and the activity of degrading USP7 protein, and can effectively inhibit malignant proliferation of acute lymphatic leukemia cells, so that the protein degradation chimera can be used for related diseases with abnormal expression of USP7 protein.

This invention discloses a drug targeting the CK1ε gene or protein for treating duveliximab intestinal toxicity, belonging to the field of pharmaceutical technology. The drug reverses duveliximab intestinal toxicity by downregulating CK1ε gene expression, inhibiting CK1ε protein function, or inhibiting CK1ε protein accumulation. This invention provides a novel therapeutic drug target for intervening intestinal toxicity caused by duveliximab. This invention proposes that the E3 ubiquitin ligase NEDD4L can ubiquitinate CK1ε and subsequently degrade it through the ubiquitin-proteasome pathway, providing a new direction for current intervention strategies for drug-induced intestinal toxicity and addressing, to some extent, the current situation of limited available intervention drugs and their singular mechanisms. The intervention drug reverses duveliximab intestinal toxicity by downregulating CK1ε, expanding the clinical application value of duveliximab.

The invention provides an application of dihydroergomine in preparation of a product for treating and / or preventing glioblastoma, and belongs to the technical field of medicines. Researches find that dihydroergomine is specifically combined with an RING structural domain of TRIM47, inhibits the activity of E3 ubiquitin linker enzyme of TRIM47, blocks the TRIM47 from inhibiting activation of STAT1 through ubiquitination modification of STAT1, and promotes activation of interferon on STAT1, so that tumor cell apoptosis is promoted, proliferation and migration are inhibited, and finally tumor growth is inhibited. Dihydroergomine has good anti-glioblastoma activity, has low toxicity to normal cells, and provides more choices and possibilities for treatment of glioblastoma.

The invention discloses a synthesis method of ubiquitin (1-74) NHNH2, and belongs to the technical field of protein synthesis. The synthesis method comprises the following steps: utilizing a prokaryotic expression system, expressing a full-length protein of Ub (1-76) and a Josephin protein coded by Burkholderia pyrrocinia by virtue of an escherichia coli BL21 (DE3) strain, hydrolyzing the Ub (1-76) by virtue of the obtained 6His-BpJOS, cutting a peptide bond between Ub Arg-74 and Gly-75, and capturing a generated thiolipid intermediate by virtue of hydrazine hydrate, so as to obtain the Ub (1-74) NHNH2. According to the present invention, the ubiquitin cleavage enzyme BpJOS catalyzed in-situ activation process is adopted, such that the preparation yield is high, the operation is simple, the large-scale preparation can be achieved, the synthesis cost is low, and the method can be used for synthesizing the multi-ubiquitination modified fragment and synthesizing the Ub (1-74) probe as the precursor, and has wide application prospects.

The present invention relates to bifunctional compounds of formula (I) useful as targeted ubiquitination modulators, in particular, PolQ modulators involved, pharmaceutical compositions comprising them, processes for their preparation and their use as therapeutic agents.

The application discloses a use of ubiquitination as a marker of systemic juvenile idiopathic arthritis, and relates to the technical field of biomedicine. The marker provided by the application is a gene combination of at least two genes in ubiquitination which participates in the occurrence of sJIA inflammation by mediating NLRs pathway; the ubiquitination includes HP, S100A9, S100A12, S100A8, IL6, CFH and UBE2D1; and the gene combination at least includes a combination of any one of HP and IL6 and UBE2D1. The application constructs a joint detection scheme of UBE2D1 and inflammatory factors, chemotactic factors or immune-related molecules, and can make up for the problems of insufficient stability or limited specificity of a single index to some extent, thereby improving the auxiliary diagnosis efficiency on sJIA. Meanwhile, the detection object involved in the application is clear, the detection mode is feasible, the detection can be carried out based on a blood sample, and the application has the advantages of relatively simple operation, strong clinical implementability, convenience for development into a detection kit, a detection chip or a matching detection reagent.

The invention provides compounds that degrade the epidermal growth factor receptor (EGFR) including mutant forms via the ubiquitination of the EGFR protein and subsequent proteasomal degradation. The compounds are useful for the treatment of various cancers.

To provide a modified human protein having improved in vivo stability.SOLUTION: There is provided a modified protein having an amino acid sequence derived from the amino acid sequence of a human wild-type protein, wherein the amino acid sequence of the human wild-type protein is modified to remove one or more ubiquitination sites identified as being present in the amino acid sequence of the human wild-type protein but absent in the homologous non-human animal wild-type protein.SELECTED DRAWING: Figure 1

The present disclosure relates to compounds and methods useful for the modulation of signal transducer and activator of transcription 6 ("STAT6") via ubiquitination and / or degradation by compounds according to the present disclosure. The present disclosure also provides pharmaceutically acceptable compositions thereof and methods of using said compositions in the treatment of various disorders.

The invention provides a polypeptide for inhibiting tumor immune escape and application thereof. The polypeptide is a peptide derived from 181-190 amino acids at the amino terminal of ubiquitin specific protease 15 (USP15), enters tumor cells by means of a cell-penetrating peptide CPP, and can obviously block the combination of USP15 and PD-L1 in the tumor cells, promote ubiquitination degradation of PD-L1, obviously lower the level of tumor cells PD-L1, inhibit tumor immune escape and play an in-vitro and in-vivo anti-tumor role. In addition, when the U10 polypeptide and the PD-1 monoclonal antibody (mAb) are jointly applied to a mouse body, the effect of synergistically resisting tumor immune escape is achieved. Therefore, the U10 polypeptide can be used as a new strategy of immune checkpoint blocking treatment, is used for tumor immunotherapy, and has important clinical application value.