233 results about "Ubiquitin" patented technology

The invention belongs to the technical field of biological medicines, and relates to a protein degradation system based on polyamide-amine dendrimers as well as a preparation method and application of the protein degradation system. The protein degradation system is of a nano-particle structure, and the nano-particle structure comprises silicon dioxide nano-particles and a polyamide-amine type dendritic polymer layer coating the surfaces of the silicon dioxide nano-particles. An MDM2 protein ligand, a GLUT1 protein ligand and an E3 ubiquitin enzyme ligand are connected to the polyamide-amine dendritic polymer layer through chemical bonds. The protein degradation system provided by the invention can be used for synergistically degrading the MDM2 protein and the GLUT1 protein. The synergistic degradation strategy not only can effectively inhibit proliferation and energy metabolism of tumor cells, but also can significantly enhance the stability of the p53 protein. By recovering the normal function of the p53 protein, the growth of tumor cells is further inhibited, and a new strategy is provided for tumor treatment.

The invention provides a functional fragment, a ubiquitin carboxyl terminal hydrolase L1 antibody and application thereof, and belongs to the technical field of antibodies. The functional fragment comprises a complementary determining region Ab1 and a complementary determining region Ab2, wherein the Ab1 comprises CDR-VL1, CDR-VL2, CDR-VL3, CDR-VH1, CDR-VH2 and CDR-VH3, and the Ab2 comprises CDR-VL1, CDR-VL2, CDR-VL3, CDR-VH1, CDR-VH2 and CDR-VH3; and the Ab2 comprises a CDR-VL1, a CDR-VL2, a CDR-VL3, a CDR-VH1, a CDR-VH2 and a CDR-VH3. The invention provides an antibody for specifically recognizing ubiquitin carboxyl terminal hydrolase L1 (Uch-L1), which has the characteristics of high specificity and high affinity, is suitable for quantitative or qualitative detection of Uch-L1, effectively reduces the detection cost of Uch-L1, shortens the detection time, improves the detection efficiency, and can realize sensitivity, stability and high sensitivity required by rapid diagnosis. And general standards such as economy and no equipment are needed.

Provided are a compound represented by general formula (I′), a method for preparing same, a pharmaceutical composition comprising same, and use thereof as a ubiquitin specific protease 1 (USP1) inhibitor, in particular, use thereof in treating or preventing a cancer.

The disclosure relates to methods for treating cancers (e.g., cancers having a BRCA1 and / or BRCA2 mutation(s)) by administering to the subject an effective amount of a ubiquitin-specific protease 1 (USP1) inhibitor.

The invention belongs to the technical field of gene engineering, and particularly relates to a medicine for treating AML (acute myelogenous leukemia) and / or prognosis of AML patients and application of ubiquitin specific protease 20 serving as a target spot in treating acute myelogenous leukemia. The invention provides a medicine for treating AML (acute myelogenous leukemia) and / or prognosis of an AML patient and application of ubiquitin specific protease 20 as a target spot in treating acute myelogenous leukemia, USP20 is used as a super enhancer regulation gene, and the progress of the AML is promoted by combining with CTNNB1, ERG, ELF1 and RUNX1. The knock-down of the USP20 can significantly inhibit AML proliferation in vivo and in vitro. The wnt-beta-catenin pathway can be influenced by interfering the expression of the USP20 so as to influence the progress of AML (acute myeloid leukemia). And the inhibition effect of the inhibitor AS1517499 subjected to virtual screening on the growth of the AML cells is superior to that of a commercial inhibitor GSK2643943A of USP20.

The invention belongs to the technical field of biological medicine, and particularly provides application of flufenidone in preparation of a medicine for preventing or treating left heart failure. The research finds that the flufenidone has the effects of relieving myocardial cell hypertrophy under a heart failure cell model and relieving myocardial hypertrophy, fibrosis and heart function deterioration of an aortic constriction animal model. According to the present invention, further research results show that fluorofenidone is directly combined with SERCA2a through Q758, D812 and E917 residues of SERCA2a so as to inhibit recognition, combination and polyubiquitination effects of WWP1 on SERCA2a, such that the protein level and the activity of SERCA2a are stabilized so as to achieve the chronic left heart failure treatment purpose. Therefore, the flufenidone serving as an active ingredient has good application prospect and application value in research and development of novel medicines for treating chronic left heart failure.

Provided herein are small molecules inhibitory compounds of ubiquitin specific protease 1 (USP1) and compositions comprising the same. Further provided herein are methods for targeting ubiquitin specific protease 1 (USP1) and methods of treating diseases or disorders related to USP1, such as cancer.

The present disclosure provides methods, pharmaceutical compositions, and kits for treating cancer in patients in need thereof. The methods comprise administering to a patient in need a small ubiquitin-like modifier (SUMO) activating enzyme (SAE) inhibitor, such as [(1R,2S,4R)-4-{[5-({4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methyl-2-thienyl}carbonyl)pyrimidin-4-yl]amino}-2-hydroxy-cyclopentyl]methyl sulfamate (Compound I-263a) or a pharmaceutically acceptable salt, in combination with one or more anti-CD19 antibodies. Also provided are medicaments for use in treating cancer.

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.

The invention belongs to the field of medicinal chemistry, and relates to carbonyl fused heterocyclic derivatives used as ubiquitin-specific protease inhibitors, in particular to a compound shown in the formula (I), an isomer thereof or pharmaceutically acceptable salt 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 present invention relates to a compound having a novel structure and ubiquitin-specific protease 1 (USP1) inhibitory activity, a stereoisomer thereof, or pharmaceutically acceptable salts thereof, use thereof for preparing a therapeutic drug, a pharmaceutical composition containing same, a therapeutic use and method using the composition, and a method for preparing same. The compound having a novel structure and USP1 inhibitory activity is represented by Formula Ia, Ib, or Ic.

The invention relates to the technical field of biomedicine, in particular to application of an E3 ubiquitin enzyme inhibitor in non-alcoholic fatty liver related drugs. The TRIM23 has obvious influence on the non-alcoholic fatty liver disease, and hepatic cell lipid deposition induced by mixing of palmitic acid and oleic acid can be improved by inhibiting expression of the TRIM23 at the cellular level; on the contrary, promoting the expression level of the TRIM23 can aggravate hepatocyte lipid accumulation induced by mixing of palmitic acid and oleic acid. Therefore, the TRIM23 inhibitor can be used for preparing the medicine for preventing or treating the fatty liver.

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 invention discloses a preparation method, application and application of a pyridazinone compound as a ubiquitin-specific protease 1 inhibitor, and particularly discloses a compound as shown in a formula (I), an optical isomer, a tautomer or pharmaceutically acceptable salt of the compound, and application of the compound as the ubiquitin-specific protease 1 inhibitor.

A compound represented by formula I and a racemate, a stereoisomer, a tautomer, an isotopic marker, nitrogen oxide, a solvate, a polymorph, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof, a pharmaceutical composition comprising same, a preparation method therefor, and a pharmaceutical use thereof are described. The compound has the activity of inhibiting USP28 and / or USP25. The structure of the formula I is as follows.

The invention relates to the technical field of daily chemicals, in particular to an anti-aging composition and application thereof. The composition is prepared from a white birch bark extract, snake venom peptide and Ectoine. The white birch bark extract promotes abnormal protein removal by activating an intracellular protein ubiquitination system, and improves the skin metabolism capability; the snake venom peptide slows down expression muscle contraction through a nerve regulation mechanism, and dynamic wrinkles are effectively faded; ectoin enhances cell membrane stability, protein protection and skin stress adaptive capacity, and under the synergistic effect of Ectoin, Ectoin and skin stress adaptive capacity, the comprehensive anti-aging effects of resisting wrinkles, tightening, relieving, brightening skin color and the like can be remarkably improved.

The invention relates to the technical field of biological medicine. The invention provides a PCSK9-targeted PROTAC oral drug as well as a preparation method and application thereof. The drug comprises the following structures: a PCSK9 binding peptide, an E3 ubiquitin ligase ligand, a cell penetrating peptide and a flexible linker. The medicine provided by the invention can be used for preparing products for treating lipid metabolism disorder diseases such as hypercholesteremia and atherosclerosis. In addition, the medicine disclosed by the invention can also be combined with statins to synergistically enhance the lipid-lowering curative effect.

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.

This invention discloses an allosteric inhibitor of the HUBL region of the USP15 protease, compound EK143, and its applications. Compound EK143, or a pharmaceutically acceptable salt, ester, optical isomer, stereoisomer, polymorph, solvate, isotope-labeled compound, metabolite, chelate, complex, inclusion compound, or prodrug thereof, acts as an allosteric inhibitor of the HUBL region (441aa-751aa) in the molecular structure of the deubiquitinating protease USP15. EK143 exhibits excellent biocompatibility and significantly enhanced antitumor activity and bioavailability.

The application belongs to the technical field of gene editing, and discloses a CBE editing protein and application. The CBE editing protein disclosed by the application is fused with a deubiquitination protein. It is found that, compared with ABE and other single-base editors, the protein of the CBE single-base editor is unstable and is rapidly degraded in cells. By fusing the deubiquitination protein, the stability of the protein of the CBE single-base editor is improved, so that the editing efficiency of the CBE is improved.

The application discloses a method and application of knocking down ubiquitin-specific peptidase 7 protein, and belongs to the field of biological medicine. The method for knocking down the USP7 protein comprises: specifically inhibiting the expression of USP7 in endothelial cells through gene intervention, and the gene intervention means comprises shRNA, siRNA or recombinant virus carrier-mediated USP7 expression down-regulation. Further provided is a USP7 knockdown reagent for preparing a drug for treating endothelial cell inflammation or a cardiovascular disease, in particular, the USP7 knockdown reagent is a USP7 knockdown virus carrier containing a Cdh5 promoter; the cardiovascular disease comprises heart failure, myocardial infarction or ischemic cardiomyopathy. The application specifically knocks down the expression of USP7 in endothelial cells through gene intervention, significantly improves the migration, tube formation capacity and reduces the apoptosis of the endothelial cells, repairs endothelial dysfunction, the USP7 knockdown virus carrier is used for preparing a drug for treating a cardiovascular disease, and has important clinical value.

The invention discloses a method for constructing a neurodevelopmental disorder animal model based on central nervous system myelin sheath function change and application, and belongs to the technical field of biological engineering. An Msl2 gene conditional knockout mouse model is constructed by adopting a gene engineering technology, the space-time specific knockout of a second exon of the Msl2 gene in a specific cell type is realized through a Cre-LoxP recombinase system, and the exon encodes a key enzyme activity region for catalyzing ubiquitination. Model construction is based on central nervous system oligodendrocyte / myelin sheath dysfunction, the behavior phenotype of the model is similar to the behavior of a typical neurodevelopment disorder animal, a brand new perspective is provided for exploring an etiology mechanism, model mice can be prepared on a large scale by performing directional mating on the gene modified mice, and the development of the model is promoted. And consistency of different experiment batches and reliable reproduction of experiment data are ensured.

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 discloses a pyrimidine compound as well as a preparation method and medical application thereof. Specifically, the invention discloses a compound shown in a general formula (I), a preparation method of the compound, a pharmaceutical composition containing the compound, and application of the compound as a ubiquitin specific protease 1 (USP1) inhibitor, especially application of the compound in treating or preventing cancers. The definition of each group in the general formula (I) is the same as that in the specification.

The invention belongs to the technical field of biological medicines, and particularly relates to application of a ubiquitin specific peptidase 13 inhibitor in preparation of a medicine for treating chronic kidney diseases. According to the present invention, as the acknowledged ubiquitin specific peptidase 13 inhibitor, the results of the in vivo unilateral ureteral ligation animal experiment and the in vitro TGF-beta 1 induced cell experiment show that the Spautin-1 can be used as the ubiquitin specific peptidase 13 inhibitor, the Spautin-1 can be used for alleviating UUO induced renal interstitial fibrosis, alleviating in-vitro TGF-beta1 induced renal fibroblast activation and regulating and controlling the cell cycle process of the TGF-beta1 induced renal fibroblast. The Spautin-1 has the advantages that the UUO induced renal interstitial fibrosis can be alleviated, and the in-vitro TGF-beta1 induced renal fibroblast activation can be alleviated; therefore, the Spautin-1 can relieve the CKD-related diseases and can be used for preparing the medicine for treating the CKD and the related diseases. The invention provides a new medicine source for relieving and treating CKD, and has a good clinical application prospect.

To provide selective targeting of ubiquitin- and ubiquitin-like E1-activating enzymes by structurally-stabilized peptides.SOLUTION: This disclosure features structurally stabilized and / or warhead-bearing structurally stabilized peptide inhibitors for targeting ubiquitin activating enzymes (E1). Methods of using such structurally stabilized peptides and warhead-bearing structurally stabilized peptides in the treatment of E1-expressing cancers or diseases or E1-dependent cancers or diseases are also disclosed. Combination therapies comprising such structurally stabilized and / or warhead-bearing structurally stabilized peptides for the treatment of E1-expressing diseases or E1-dependent diseases are also provided.SELECTED DRAWING: None

Provided herein are bifunctional compounds with a moiety or domain that is a binder of the ubiquitin receptor RPN13 and another moiety or domain that is a binder of a target protein DOT1L to induce degradation of DOT1L. Also provided are pharmaceutical compositions comprising the bifunctional compounds, and methods of treating and / or preventing diseases (e.g., proliferative diseases, such as cancers). Provided also are methods of inducing the degradation of DOT1L by administering a bifunctional compound or composition described herein, wherein one domain of the bifunctional compound is a binder of the ubiquitin receptor RPN13 and another domain of the compound is a binder of the target protein DOT1L in a subject.

JPEG2026525352000192.jpg3981 The present invention relates to compounds of formula (I) that are useful as inhibitors of ubiquitin-specific protease USP19 activity. The present invention also relates to pharmaceutical compositions comprising these compounds and methods of using these compounds in therapeutics.

The application discloses a ubiquitin transporter AcRAD23D1, a coding gene and application thereof, and belongs to the technical field of genetic engineering. The application clones an AcRAD23 family gene AcRAD23D1 from a kiwi fruit, and compares phenotypes and determines physiological parameters under transgenic and drought stress treatment, and identifies biological functions of the gene in positive regulation of drought resistance of the kiwi fruit in detail. The research result has important theoretical significance and practical application value for carrying out molecular directional breeding of the kiwi fruit. The overexpression transgenic kiwi fruit plant obtained by using the agrobacterium-mediated maceration method has significantly increased drought stress resistance, the transgenic kiwi fruit plant with silenced expression has significantly reduced drought stress resistance, and the application has important application value in molecular directional breeding of the kiwi fruit and reduction of cultivation environment limitation.