23 results about "Proteasome degradation" patented technology

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 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 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.

Provided herein are compounds (e.g., compounds of Formula (Ia)) that function to recruit LRRK2 protein or a mutated version thereof to an E3 ubiquitin ligase for targeted ubiquitination and subsequent proteasomal degradation.

The invention discloses an application of harpagide in preparation of a medicine for inhibiting STUB1. The harpagide can be used as a specific inhibitor of E3 ubiquitin ligase STUB1. By inhibiting the STUB1, the harpagide can effectively block the GR ubiquitination process mediated by the STUB1, so that the GR is prevented from being degraded by the proteasome, and the stability of the GR protein level is finally realized. Through combined application of harpagide and glucocorticoid, the treatment effect of hormone in a noise-induced hearing loss animal model can be remarkably improved, and the treatment effect is better than that of treatment by independently using hormone.

The invention provides a bifunctional protein degradation agent for directly targeting proteasome, and a preparation method and application thereof. The bifunctional protein degradation agent comprises a POI ligand for specifically binding to a to-be-degraded target protein related to a disease; the proteasome ligand is used for specifically binding a protein degradation tool proteasome; and a linker chain moiety linking the proteasome ligand to the POI ligand. Specifically, according to the degradation technology, degradation is achieved by directly collecting POIs near intracellular proteasomes. The invention establishes a novel targeted protein degradation technology platform, and provides a method for preparing the protein degradation agent at the same time. The invention also has the advantages that the compound molecule not only recruits POI to proteasome, but also can improve the hydrolytic activity of the proteasome and enhance the degradation efficiency of the POI. And the proteasome is highly expressed in all cells, and tissue specificity does not exist, so that the direct targeting proteasome degradation agent in the technology can be widely applied.

This invention discloses the use of LAPTM5 in the preparation of drugs regulating renal tubular epithelial-mesenchymal transition (EMT). Through bioinformatics analysis and multi-level experimental verification, this invention found that LAPTM5 is significantly upregulated in an aging kidney model and is positively correlated with renal aging and the severity of fibrosis. Mechanistic studies show that LAPTM5 interacts with the deubiquitinating enzyme USP10 and promotes its lysosomal degradation, weakening the deubiquitination effect of USP10 on PTEN. This leads to proteasomal degradation of PTEN via the K48-linked polyubiquitination pathway, thereby relieving PTEN's inhibition of the PI3K / AKT / mTOR signaling pathway, inhibiting autophagy activity, promoting renal tubular epithelial-mesenchymal transition, and accelerating the process of renal fibrosis. At the cellular level, PTEN overexpression can rescue LAPTM5-induced EMT; in animal models, the PTEN agonist matrine significantly improves D-galactose-induced renal fibrosis in aging mice and protects renal function by restoring autophagy.

The invention belongs to the technical field of biological medicines, and particularly relates to application of GLRX5 in preparation of a medicine for enhancing immunotherapy of renal cell carcinoma. GLRX5 is a tumor inhibition factor in renal cell carcinoma and a key factor for regulating and controlling the stability of renal cell carcinoma PD-L1, can inhibit proliferation and metastasis of renal carcinoma, specifically interacts with PD-L1, and inhibits immune escape of renal carcinoma by enhancing SPOP-mediated PD-L1 K48 connection ubiquitination and proteasome degradation, so that treatment of an immunosuppressor is enhanced; the molecular mechanism determines that the GLRX5 is used as a key coordination factor of an SPOP-PD-L1 degradation axis in a renal cell carcinoma pathogenesis, also reveals that the GLRX5-SPOP-PD-L1 axis is a key mechanism of RCC immune escape, and provides a new strategy for promoting PD-L1 degradation and reversing immunosuppression by enhancing the expression or activity of the GLRX5.

The invention provides application of xanthophyll in preparation of drugs for inhibiting breast cancer cell proliferation and a pharmaceutical composition for inhibiting breast cancer. The pharmaceutical composition comprises xanthophyll and cis-dichlorodiammineplatinum. The xanthophyll and cis-platinum combined use has the effect of synergistically inhibiting breast cancer cell proliferation, and the action mechanism is as follows: the xanthophyll and cis-platinum act on GSK-3beta in a targeting manner, the phosphorylation level of GSK3beta-Ser9 site is reduced, the biological activity of GSK-3beta is activated, then phosphorylation of beta-catenin is promoted, the phosphorylated beta-catenin is degraded by proteasomes, and the proliferation of breast cancer cells is inhibited. Finally, abnormal activation of a Wnt signal channel is inhibited, and the effect of inhibiting growth of breast cancer cells is achieved. The new mechanism that xanthophyll plays an anti-tumor role by regulating and controlling a GSK-3beta signal channel provides an important theoretical basis for developing breast cancer targeted therapy drugs based on natural products, provides a new drug combination scheme for treating breast cancer, is high in safety and small in side effect, and has important clinical application value and development prospects.

This article provides compounds (e.g., compounds of formula (la)) that recruit LRRK2 protein or its mutant form to E3 ubiquitin ligases for targeting ubiquitination and subsequent proteasome degradation.

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 discloses application of an FMR1 inhibitor in preparation of a medicine for treating immunological rejection type gastric cancer. Experimental studies prove that FTO is continuously and highly expressed in immunological rejection phenotypes and is related to interstitial activation and T cell rejection. Continuous immunohistochemistry and multiple immunofluorescence show that the FMR1 protein is highly expressed in an immunological rejection type tumor microenvironment, and most CD8 + T cells are located in tumor interstitial substances. In mechanism, the FMR1 regulates and stabilizes FTO protein and limits the degradation of proteasome of the FTO protein through post-translation, so that FTO-dependent m6A reprogramming is maintained, and an immunological rejection microenvironment is enhanced. Therefore, the invention discloses a non-classical mechanism that the FMR1 modifies and stabilizes the FTO protein after translation, and the FMR1-FTO axis can be used as a potential intervention target for breaking an immune barrier and sensitizing gastric cancer immunotherapy.

The invention belongs to the technical field of biological medicines, and provides application of DHODH-CHKalpha-TRIM28 in screening of medicines for inhibiting proliferation or growth of colorectal cancer cells. The prognosis of colorectal cancer patients with high coexpression of DHODH and CHKalpha is poor; dual targeting inhibition of DHODH and CHKalpha can synergistically inhibit proliferation or growth of colorectal cancer cells. DHODH is competitively combined with an F242 / N243 structural domain of CHK alpha, so that TRIM28 is spatially hindered from approaching a K244 residue on the CHK alpha, and the ubiquitination of the CHK alpha at the K244 site mediated by the TRIM28 and the subsequent proteasome degradation process of the CHK alpha are inhibited. The CHKalpha stability increase mediated by DHODH drives the accumulation of carcinogenic phosphatidylcholine, and promotes the proliferation of colorectal cancer cells and the growth of tumors. Flurmide and MN58b are jointly used for dual targeting of DHODH and CHKalpha, and growth of colorectal cancer is synergistically inhibited. It is revealed that the DHODH-CHKalpha-TRIM28 axis is a key metabolic susceptible pathway.

To provide compounds that degrade epidermal growth factor receptor (EGFR), including mutant forms, by ubiquitination of the EGFR protein and subsequent proteasomal degradation. The compounds are useful in the treatment of a variety of cancers.SOLUTION: The compound is represented by formula (I) having a specific substituent.SELECTED DRAWING: None

This application relates to bifunctional compounds, their preparation methods, pharmaceutical compositions, and uses. The compounds have the following general formula: The compounds designed in this application include a portion that binds to HIF-2α protein and a portion that binds to E3 ubiquitin ligase CRBN, which are coupled or linked by a linker L. The compounds of this application can recruit HIF-2α to the ubiquitin ligase using the ubiquitin-proteasome system in the body's cells, ubiquitinate HIF-2α, and then degrade it by the proteasome in the body's cells, thereby reducing the expression level of HIF-2α in tumor cells, and thus can be used to treat diseases related to high expression of HIF-2α.

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.

The application discloses application of DNMT3B as a marker in preparation of a severe EV71 infection diagnosis product, and belongs to the biomedical field. It is found by the application that the nucleocytolysis degree and ubiquitination level of DNA methyltransferase DNMT3B can be used for diagnosing children with severe EV71 infection. EV71 infection promotes partial transport of DNMT3B in the cell nucleus to the cytoplasm, and promotes K63 ubiquitination modification of DNMT3B by combining the 3C and 3D proteins with DNMT3B, so that DNMT3B is finally degraded by a proteasome. The reagent for detecting the nucleocytolysis degree of DNMT3B and / or the reagent for detecting the ubiquitination level of DNMT3B can be used for preparing a severe EV71 infection diagnosis product or a severe EV71 infection prognosis diagnosis product, so as to realize diagnosis of severe EV71 infection or prognosis thereof.

The present application relates to the technical field of medicines, and specifically relates to a CRBN binding compound for degrading a target protein and a use of the compound. In the present application, a bifunctional compound containing a target protein binding moiety and an E3 ubiquitin ligase (such as CRBN) binding moiety is directionally bound to a target protein and CRBN, such that the protein is placed in close proximity to E3, the ligase mediates ubiquitination of the target protein, and then the target protein is degraded by a proteasome. The compound has a structure represented by formula (A), wherein the definition of each group is the same as that in the description.

The invention belongs to the technical field of biological medicines, and relates to application of a histone deacetylase inhibitor HDACi in preparation of a medicine for preventing and / or treating hyperammonemia-induced encephalopathy. According to the invention, a histone deacetylase inhibitor HDACi is used as a new medicine, the HDACi can enter a central nervous system, and the GS is triggered to be degraded through a proteasome mediated by CRBN E3 ubiquitin ligase by improving the acetylation level of a key enzyme, namely glutamine synthetase (GS), of astrocytes, so that the GS protein abundance is reversibly reduced, and the GS protein abundance is reduced. The application has the advantages that pathological accumulation of toxic metabolite glutamine can be reduced from the source, cerebral edema, autophagy-lysosomal dysfunction, neuroinflammation and neuron injury caused by the pathological accumulation can be synchronously improved, severe neurotoxicity such as persistent enzyme inhibition and acute epilepsy caused by irreversible inhibitors such as MSO can be avoided, clinical transformation risks can be obviously reduced, and the safety is high.

The present invention provides compounds that degrade Kirsten rat sarcoma viral oncogene homolog (KRAS) proteins, including mutant forms, through ubiquitination and subsequent proteasomal degradation of the KRAS protein. The compounds can be used to treat various cancers.

The present invention relates to an inhibitor of heat shock protein 90. Disclosed are a heat shock protein 90-based bivalent inhibitor, and a preparation method therefor and the use thereof. The bivalent inhibitor is a compound having a structural formula as shown in formula I: A-L-B Formula I, or a pharmaceutically acceptable salt, solvate, or optical isomer thereof, wherein A and B are ATP inhibitors of heat shock protein 90, and the motif structure of L is a flexible linker group of PEG or alkanes, or a rigid linker group comprising aryl, heteroalkyl, or heteroaryl. The bivalent inhibitor can effectively inhibit the activity of molecular chaperone HSP90, hinder the folding and modification of a substrate protein, degrade the substrate protein via a ubiquitin-proteasome degradation pathway, induce non-native dimerization of HSP90, and interfere with protein-protein interactions associated with HSP90. In addition, the bivalent inhibitor reduces the heat shock response induced by HSP90 inhibition, and exhibits potent activity in degrading the substrate protein.

This invention discloses the application of a protein conjugate in membrane protein degradation and a method for membrane protein degradation. The protein conjugate comprises a carrier and an antibody; the antibody can be effectively conjugated to a multivalent antibody via the carrier; membrane protein degradation includes the protein conjugate mediating the cross-linking of the target protein to form aggregates, followed by degradation of the target protein via the proteasome and / or lysosome degradation pathways. This protein conjugate can effectively degrade membrane proteins, and throughout the process, it does not rely on degradation ligands targeting the proteasome or lysosome receptor, thus possessing strong applicability.

Provided herein are bifunctional compounds that bind tau protein and / or promote targeted ubiquitination for the degradation of tau protein. In particular, provided are compounds that can bind tau protein, a protein whose aggregation is implicated in a variety of neurodegenerative disease (e.g., tauopathies), and can promote its degradation by recruiting an E3 ubiquitin ligase (e.g., Cereblon), which can ubiquitinate tau protein, marking it for proteasomal degradation. Also provided are radiolabeled forms of the bifunctional compounds, pharmaceutical compositions comprising the bifunctional compounds, methods of detecting and / or diagnosing neurological disorders, methods of detecting and / or diagnosing pathological aggregation of tau protein (e.g., in the central nervous system), methods of treating and / or preventing neurological disorders, and methods of promoting the degradation of tau protein by E3 ubiquitin ligase activity in a subject by administering a compound or composition described herein.