149 results about "Ubiquitin" patented technology

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 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.

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 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.

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.

The invention relates to the technical field of biology, and discloses a recombinant N-acetylglucosamine-1-phosphate uridine transferase (GlmU) mutant and a preparation method thereof. The sequence of the recombinase is formed by connecting an N-acetylglucosamine-1-uridine phosphate transferase (GlmU) mutant (L113V-V172I) from Azotobacter chroococcum, an N-terminal histidine tag (His-tag) and a small ubiquitin-like modified protein tag (SUMO-tag) in series. The invention further discloses a preparation method of the recombinase. Compared with a recombinant wild type N-acetylglucosamine-1-uridine phosphate transferase with the same source, the recombinant N-acetylglucosamine-1-uridine phosphate transferase mutant has higher activity which is 1.5 times of that of the recombinant wild type and higher stability, and the residual activity of the mutant is 66.5% after the mutant is placed at room temperature for 5 days, so that the mutant has a good application prospect in the field of N-acetylglucosamine-1-uridine phosphate transferase. And the soluble expression quantity of the recombinant mutant N-acetylglucosamine-1-uridine phosphate transferase is increased by 5 times.

This invention relates to the field of pharmaceutical technology, specifically to ubiquitin-specific protease 1 inhibitor compounds, pharmaceutically acceptable salts, esters, deuterated derivatives or stereoisomers thereof, pharmaceutical compositions and formulations containing said compounds, pharmaceutically acceptable salts, esters, deuterated derivatives or stereoisomers thereof, methods for preparing said compounds, pharmaceutically acceptable salts, esters, deuterated derivatives or stereoisomers thereof, and the use of said compounds, pharmaceutically acceptable salts, esters, deuterated derivatives or stereoisomers thereof in the preparation of medicaments for the treatment and / or prevention of USP1-mediated diseases and related diseases.

Disclosed herein are methods of aiding in the diagnosis and evaluation of a subject that has sustained or may have sustained an injury to the head. For example, the present disclosure provides methods for aiding in the diagnosis and evaluation of a subject to determine whether the subject has sustained a traumatic brain injury (TBI) by detecting or measuring a combination of the levels of ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) in samples taken at various time points within 48 hours after the subject has sustained or may have sustained an injury to the head.

The invention provides an MITF protein degradation agent and application thereof, and particularly provides a compound or a pharmaceutically acceptable salt thereof, or a stereoisomer or a prodrug thereof, and the compound is shown as a formula (I). The compound can degrade MITF 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 MITF protein.

The application discloses a preeclampsia diagnosis and treatment biological marker and application thereof; the application deeply demonstrates the mechanism that high expression DHRS4 causes PE by inhibiting the invasiveness of trophoblasts from the clinical sample, cells and in vivo level, and overexpression DHRS4 in the application combines and up-regulates LONP2, degrades TFAM protein through ubiquitination, causes mitochondrial dysfunction, weakens the migration and invasion ability of trophoblasts, participates in the mechanism of PE occurrence, is a new mechanism clue obtained according to the pre-experiment results and information analysis, is a new target for deeply exploring the clinical diagnosis and treatment of PE, and the research result can provide a theoretical basis for guiding the early prediction and intervention of PE in the future.

This invention provides methods of detecting biomarkers in the biofluid of sepsis-associated encephalopathy (SAE) patients, including but not limited to glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase LI, Tan protein, Neurofilament light chain (NF-L), myelin basic protein (MBP), secretogranin, Copeptin, total all-spectrin, all-spectrin breakdown products (SBDP, including SBDP145, SBDP150, SBDP120 all-spectrin N-terminal fragment or SBDP150N), neuron specific enolase (NSE), mature brain derived neurotrophic factor (BDNF), and full-length Pro-BDNF. These biomarker peptides are markers of axonal and blood brain barrier integrity which can be used to diagnose SAE and to assess and predict cognitive performance and outcomes in acute presentations of sepsis.

The invention relates to a mild anti-aging liposome skin care composition suitable for sensitive skin and application of the mild anti-aging liposome skin care composition, and belongs to the technical field of cosmetics. According to the lipidosome skin care composition, a specific space structure is adopted, that is, PDRN is wrapped in an inner water phase of lipidosome, a white birch bark extract and a tephrosia rubescens seed extract are embedded into phospholipid double layers of the lipidosome, and VII type collagen is anchored to the outer side surfaces of the phospholipid double layers of the lipidosome, so that a skin cell ubiquitination system is synergistically regulated by multiple target points, and the skin cell ubiquitination effect is improved. Therefore, the stable state of protein is systematically recovered, and light aging and initial aging of the skin are comprehensively resisted from the aspects of tightening, wrinkle resisting, soothing, repairing, skin elasticity improving, barrier repairing, skin color brightening and the like.