143 results about "Proteasome" patented technology

The invention provides a KRAS G12D protein degradation agent and application thereof in medicine, and particularly provides a compound with a structure as shown in a formula (I) and application of a stereoisomer or a prodrug molecule containing the compound or pharmaceutically acceptable salt of the compound as medicine. The compound can degrade KRAS G12D protein in a targeted manner through a ubiquitin-proteasome way, so that the compound can be used for treating indications mediated by abnormal expression of the KRAS G12D protein. Wherein each group in the formula (I) is defined in the specification. # imgabs0 #

The present disclosure provides bifunctional compounds Formula (IA) as selective SMARCA2 degraders via ubiquitin proteosome pathway, and their therapeutic use for treating cancers.

The invention provides heterobifunctional compounds comprising an effector protein binding moiety selected from mTor, PLK1, CDKI, CDK2, CDK9, BRD4, AURKA, AURKB, MEK, Src, c-KIT, KIF11, HSP90, tubulin, proteasome, topoisomerase or HD AC which is linked to a moiety that binds to a target protein selected from KRAS, HER2 or EGFR. Pharmaceutical compositions and their use in treating disease, such as cancer, are also disclosed.

The invention discloses a colorectal cancer radiotherapy sensitization medicine and application thereof, belongs to the field of biological medicine, and particularly relates to a colorectal cancer radiotherapy sensitization medicine which comprises active pharmaceutical ingredients and a solvent, the active pharmaceutical ingredients comprise doxorubicin and a nitrogen-containing compound, the nitrogen-containing compound comprises quinoline-6-carbohydrazide and N-benzyloxymethyl-4-nitroimidazole, and the nitrogen-containing compound comprises quinoline-6-carbohydrazide and The colorectal cancer radiotherapy sensitization medicine disclosed by the invention focuses on a key driving gene FOXP4 for colorectal cancer radiotherapy resistance, and FOXP4 protein is degraded through a ubiquitin-proteasome way, so that not only can the sensitivity of tumor cells to radiotherapy be remarkably improved and tumor growth be inhibited, but also damage to normal tissues is reduced; moreover, the problem of drug resistance easily generated by a traditional method is effectively avoided, the research and development cost is greatly reduced, clinical transformation is accelerated, and the method has a good clinical application prospect.

The invention relates to the field of 26S proteasome inhibition and modulation by niclosamide and to a method for treating diseases related to increased proliferation, immune system, inflammation and neurodegenerative disorders by inhibition and modulation of the 26S proteasome in living cells, and to a niclosamide-containing compound for use in this treatment.

The invention discloses PROTAC capable of efficiently degrading a target protein and a preparation and delivery method of the PROTAC, a phase separation sequence and a designed double-targeting molecule are fused to respectively target the target protein and a proteasome, and phase separation of the PROTAC and the target protein is realized, so that efficient degradation of the target protein is realized. In addition, the delivery of PROTAC is also realized by encapsulating mRNA with LNP, and the target protein can also be efficiently degraded in cells, so that a way is also provided for the delivery of peptide or protein PROTAC into the human body.

Proteolysis Targeting Chimeras (PROTACs) are heterobifunctional degraders that specifically eliminate targeted proteins by hijacking the ubiquitin-proteasome system (UPS). Provided are pharmaceutical compositions which include a mixture of a PROTAC, a hydrophilic polymer, a surfactant, and optionally an acid and an adsorbent. Also described are methods for preparing and using such pharmaceutical compositions. In one aspect, disclosed herein is an amorphous solid dispersion comprising PROTAC.

A series of recombinant DNA constructs and a method is disclosed for use in immunological therapy in general; and in disrupting T cell receptor (TCR), human leukocyte antigens (HLA) class I and NKG2D (Natural-Killer Group 2, member D) ligand expression in particular, with the effect of producing highly compatible autologous universal T cells for further genetically engineering for allogeneic administration. A Universal T (UT) construct is provided and used, comprising a TCR antibody fragment fused to a transmembrane domain (TMD) and ER retention domain of adenovirus early region 3 glycoprotein E3-19k (E3 / 19K) (TCR-E3 / 19K RD). The Universal T (UT) construct can hijack ERAD machinery to arrest TCR and HLA molecules in endoplasmic reticulum (ER) and facilitate their translocation into the cytoplasm for ubiquitination and degradation by proteasomes.

The proteolytic targeting chimera (PROTAC) is a heterobifunctional degradation agent that specifically eliminates the targeted protein by hijacking the ubiquitin-proteasome system (UPS). Pharmaceutical compositions comprising PROTAC, a hydrophilic polymer, a surfactant, and optionally a mixture of an acid and an adsorbent are provided. Methods for making and using such pharmaceutical compositions are also described. In one aspect, disclosed herein is an amorphous solid dispersion comprising PROTAC.

The present invention relates to the field of biomedicine, and mainly relates to a vaccine design method for enhancing an antigen-presenting effect. A target antigen and a ligand such as a polypeptide or a protein domain having an E3 ubiquitin ligase binding or recruitment function are jointly coded in a same nucleic acid sequence, thereby promoting the degradation of the antigen protein by means of a proteasome approach, increasing the number and abundance of antigen peptides having antigen epitopes, and forming more peptide-MHC (p-MHC) complexes, and the complexes are presented on the surfaces of the cells, thereby enhancing subsequent immune response, and exerting an efficient tumor immunotherapy effect. The nucleic acid, the protein and the polypeptide vaccine provided have an efficient antigen-presenting effect and strong immunogenicity, and have good clinical application prospects.

The invention discloses dsRNA / fused dsRNA and application of the dsRNA / fused dsRNA in prevention and treatment of spider mites, the dsRNA is dsRpt3, and the fused dsRNA is obtained by fusing dsRNA of a plurality of genes of the same gene family of targeted spider mites; the gene family is selected from a proteasome ATP enzyme family and an apolipoprotein family; the nucleotide sequence of one chain of the fused dsRNA is as shown in any one of SEQ ID NO.1-4. The invention also discloses a preparation method of the fused dsRNA. Compared with the existing dsRNA for preventing and treating a single variety of spider mites, the dsRNA / fused dsRNA can prevent and treat various spider mites at the same time, is expected to be applied to preparation of biopesticides for preventing and treating spider mites, reduces the use of chemical pesticides, protects the environment, and reduces the damage of the chemical pesticides.

The invention discloses 5 alpha-reductase degradation molecules as well as a preparation method and application thereof, four 5 alpha-reductase degradation molecules can realize thorough removal of zymoprotein by inducing proteasome-dependent degradation of 5 alpha-reductase instead of only inhibiting the activity of the 5 alpha-reductase, so that a more lasting treatment effect is obtained; under the condition of equal dosage, the effect of the 5 alpha-reductase degradation molecule on treating the benign prostatic hyperplasia is superior to that of the traditional inhibitor finasteride; the four kinds of 5 alpha-reductase degrading molecules can effectively degrade 5 alpha-reductase protein and remarkably inhibit development of benign prostatic hyperplasia, have good biological safety and provide new strategies and candidate drugs for treatment of diseases related to 5 alpha-reductase such as benign prostatic hyperplasia, prostatic cancer, androgenetic alopecia and acne.

Disclosed herein are multifunctional polypeptides comprising an optional signal peptide sequence, a cell penetrating peptide, an antigen binding domain (e.g., anti-synuclein, anti-tau, anti-huntingtin), and a programmable proteasome-targeting PEST motif, and methods for using these polypeptides in treatment of protein aggregation diseases, e.g., neurodegenerative diseases.

Disclosed is a method of treating a neurodegenerative disease such as Parkinson's disease, diffuse Lewy body disease, transitional Lewy body dementia, and multiple system atrophy in a subject. The method comprises administering to the subject a therapeutically effective amount of a peptide comprising an α-synuclein binding domain operably linked to a protein transduction domain and a proteasomal targeting domain, wherein the α-synuclein binding domain is derived from a reversed sequence of β-synuclein. Other methods, as well as uses and compositions, are disclosed.

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.

This invention discloses a PROTAC chimera for targeted degradation of ALKBH5, its preparation method, and its applications. The structural formula of the PROTAC chimera is shown in Formula I. The PROTAC chimera provided by this invention achieves specific ubiquitination modification and proteasome-dependent degradation of the ALKBH5 protein, completely eliminating the target protein function from its source. This invention overcomes the inherent limitations of traditional small molecule inhibitors, which can only reversibly block ALKBH5 enzyme activity, cannot eliminate the target protein, easily induce compensatory upregulation of the target protein, and develop drug resistance. It provides a novel and precise targeted therapy strategy for ALKBH5-driven malignant tumors.

Provided herein is an epoxyketone peptide immunoproteasome inhibitor having a structure: Formula (I) wherein X is a counterion, crystal forms, salts and processes for its preparation, and compositions thereof.

Compounds (I), compositions, and methods for use in degrading Aurora kinase are disclosed. The compounds, compositions, and methods can be used to modulate the immune system, to treat diseases amenable to immune system modulation, and for treatment of cells in vivo, in vitro, or ex vivo. Also disclosed are pharmaceutical compositions comprising Aurora kinase degraders, as well as methods for treating cancer using Aurora kinase degraders.

The compounds of the present invention are represented by the following compounds having Formula I:where the substituents R1, R4, L, M, X, Y, and s are as defined herein. The compounds of the present invention are also represented by the following compounds having Formula (Ia), Formula (Ib), or Formula (Ic):where the substituents R1-R4, Rx, Ry, X, Y, and s are as defined herein.These compounds are used in the treatment of cancer, immunologic disorders, autoimmune disorders, neurodegenerative disorders, or inflammatory disorders or for providing immunosuppression for transplanted organs or tissues.

Levels of expression of antibiotic resistance genes are increased up to six-fold by inserting a proteasome-targeting tag into transgenes expressed in eukaryotic cells. Various selectable marker proteins are combined with different destabilization domains, leading to up to 70% increase in transgene expression. The increase in expression varies highly depending on the engineered construct and the lines cells used. Increase in expression drives exosome loading of cargo proteins in some aspects. By increasing expression and by editing trafficking signals of cargo proteins, proteins that normally locate to the ER can be trafficked to exosomes. This disclosure discloses efficient exosome delivery of a wide variety of engineered proteins, including modified antigen proteins of SARS-CoV-2 and influenza, and other proteins such as a modified alpha galactosidase A, an extracellular domain of vascular endothelial growth factor fused to a constant region of a human immunoglobulin heavy chain, and modified trastuzumab heavy and light chains.

This invention provides novel small molecule non-ubiquitin proteolysis targeting chimera NuTAC, which degrades any selected proteins by directly tethering to the proteasome, processes for the preparation thereof, and its uses in medicine. This invention particularly provides NuTAC molecules with a binder of the proteasomal substrate receptor Rpn13 and a binder of the target protein PD-L1 or BRD4 to induce degradation of target proteins and suppress tumor growth. Also provided are an Rpn13 binder as well as an inhibitor RPI-5, which additionally induces phosphorylation of Rpn13, Src-3 and FBXO2, and another Rpn13 binder NuL1 that does not induce phosphorylation of above proteins. Also provided are pharmaceutical compositions comprising the bifunctional compounds, methods of treating and / or preventing diseases (e. g., cancers), and methods of developing reagents to deplete cellular proteins.

The present invention discloses a negative regulation mechanism, experimental method and application of the Agrin-MuSK-DOK7 signaling pathway. After Agrin stimulates myotubes to activate MuSK, MuSK promotes phosphorylation of DOK7 Tyr106. With the help of CDH1, APC2 binds to DOK7 phosphorylated at Tyr106 and mediates ubiquitination of DOK7 Lys243 mainly in the form of K48 connection, promoting the degradation of DOK7 through the proteasome system, and ultimately leading to downregulation of DOK7 protein level, thereby achieving negative regulation of the Agrin-MuSK-DOK7 signaling pathway. In the present invention, APC2 CDH1 By promoting the ubiquitination and degradation of DOK7, negative regulation of the Agrin-MuSK-DOK7 signaling pathway is achieved, avoiding excessive activation of the Agrin-MuSK-DOK7 signaling pathway leading to abnormal NMJ development. The present invention provides a new theoretical basis for a deeper understanding of the molecular mechanism of neuromuscular junction development, and also provides new ideas for the development of treatment methods for related diseases.

The invention relates to the technical field of medicines, in particular to application of huperzine A in treatment of beta-thalassemia. It is found for the first time that the anti-Alzheimer disease drug huperzine A can be directly combined with gamma-globin to inhibit degradation of gamma-globin through a ubiquitin-proteasome pathway, so that the stability of gamma-globin and the fetal hemoglobin level are improved; the abnormal erythropoiesis and hemolysis phenotype of the beta-thalassemia are improved under the condition of not changing the mRNA expression. Animal experiments show that huperzine A obviously improves hematocrit and the number of red blood cells, reduces the size distribution width of the red blood cells and the proportion of reticulocytes, relieves oxidative stress, hemolysis, splenomegaly and iron overload, and has no obvious liver and kidney toxicity. The invention creatively provides a new strategy for improving HbF by regulating and controlling protein homeostasis instead of transcriptional up-regulation, and provides a new drug action mechanism and application direction for treatment of beta-thalassemia and other hemoglobin diseases.

The present invention relates to a method for determining the efficacy of a drug treatment for a subject suffering from malignant melanoma, wherein said method comprises the steps of: (i) evaluation of the presence or absence of a genetic alteration in a BRAF gene, a. detecting the presence and / or quantity of at least one biomarker in a biological sample obtained from said subject, wherein said biomarker is BRAF V600 mutated protein and / or at least one immunoproteasome protein, and b. classifying the subject as having a high or low likelihood of responding to a drug treatment, based on the presence and / or quantity of said at least one biomarker, wherein in case the genetic alteration in the BRAF gene is present, the presence and / or quantity of at least one BRAF V600 mutated protein and at least one immunoproteasome protein is detected in said biological sample, and wherein in case the genetic alteration in the BRAF gene is not present, the presence and / or quantity of at least one immunoproteasome protein is detected in said biological sample.

The invention discloses application of deaminotyrosine in improvement or prevention and treatment of muscular atrophy, and relates to the technical field of biological medicines. The invention finds that in the cellular level, DAT can effectively resist C2C12 myoblast senescence induced by etoposide; in a dexamethasone-induced C2C12 myotube atrophy model, DAT not only inhibits myotube diameter reduction from the form, but also down-regulates mRNA expression of key atrophy genes Atrogin-1 and MuRF-1 from the molecular level, and inhibits excessive activation of a ubiquitin-proteasome system; in-vivo animal experiments prove that DAT can reverse aging-related dyskinesia of rapidly-aged SAMP8 mice, and gait parameters of the rapidly-aged SAMP8 mice are all remarkably improved. According to the invention, a complete evidence chain from cells to the whole is constructed, and the DAT is proved to improve the senescent skeletal muscle atrophy through multiple ways of intervening cell senescence, antagonizing protein degradation, improving muscle microenvironment and the like, and shows important potential application value.

The invention provides SETDB1-targeting PROTAC as well as a preparation method and application thereof, and relates to the technical field of clinical medicine. The PROTAC comprises a nucleic acid aptamer capable of being specifically combined with SETDB1 protein, a connexon and a ligand for recruiting E3 ubiquitin ligase, wherein the ligand for recruiting the E3 ubiquitin ligase is thalidomide. The PROTAC can recruit the E3 ligase CRBN in cancer cells onto the SETDB1, and degrade the SETDB1 in a proteasome dependent manner. Therefore, the PROTAC can inhibit proliferation and migration of cancer cells; the killing effect of CD8 + T cells on cancer cells is enhanced, and the growth of the cancer cells is inhibited. Tests prove that the potential application of the PROTAC based on the aptamer in SETDB1 degradation in tumor cells provides a promising strategy for cancer treatment.

This disclosure relates to compounds of formulae I, II and III useful for degrading ITK via a ubiquitin proteolytic pathway. This disclosure also provides pharmaceutically acceptable compositions comprising said compounds, and methods of using the compositions in the treatment of various diseases, conditions, and / or disorders.

The present invention provides a use of a novel chromone derivative as a preventive and therapeutic agent for fibrosis. The compound can effectively prevent, ameliorate, or treat fibrosis by inhibiting TGF-beta signaling and inducing autophagy, by means of proteasome inhibition.

The invention discloses application of carfilzomib in preparation of a medicine for preventing and treating Nipah virus, and belongs to the technical field of medicine. The method mainly aims at ubiquitination modification of nipah virus M protein, the carfilzomib is used for inhibiting a host proteasome path, free ubiquitination factors in cells are depleted to achieve the effect of inhibiting ubiquitination of the M protein, then nucleoplasm shuttle of the M protein is inhibited, replication of the nipah virus is inhibited, and the effect is good. At present, most of research and development of virus medicines and vaccines are designed or modified aiming at viruses, a new thought is provided for research and development of medicines and vaccines in the future, and a new application is also provided for Carfilzomib.

This invention provides the application of chlorogenic acid in the preparation of drugs for treating intranuclear inclusion body disease (NIID), belonging to the field of pharmaceutical technology. This invention utilizes widely available sources with abundant safety data. Compared to novel chemical entities, chlorogenic acid, with its lower development risk, is used as a raw material. It has been found that chlorogenic acid can enhance the interaction between polyG protein and the E3 ubiquitin ligase TRIM21, forming a stable TRIM21-chlorogenic acid-polyG ternary complex. This promotes polyG ubiquitination and proteasome-dependent degradation, thereby reducing intracellular inclusion body burden and alleviating NIID from its pathological root cause. This provides a safe, effective, and highly specific new targeted therapeutic strategy for NIID.