462 results about "Ubiquitin" patented technology

The invention provides application of a PARPi sensitizer in treatment of malignant tumors, and particularly relates to the technical field of biological medicines. A large number of experiments prove that TRMT10A is crucial for recruitment from BRCA1 to DNA damage sites for the first time, so that HR repair is promoted. The deletion of TRMT10A inhibits HR repair, so that tumor cells are more sensitive to PARPi. The invention discloses that the expression of TRMT10A in mCRPC is up-regulated, and the TRMT10A is regulated and controlled by ubiquitin specific peptidase 10 (USP10). Spautin-1 significantly results in the deficiency of TRMT10A, and sensitizes the tumor to PARPi in both patient-derived xenograft (PDX) and cell-derived xenograft (CDX). The research reveals that the ATM-TRMT10A-BRCA1 axis plays an important role in sensibilization of the PARP inhibitor, and a new angle is provided for exploring synthesis lethality. The mechanism can be therapeutically utilized through the combination of PARPi and Spautin-1, which may benefit more extensive patients with non-BRCA malignant tumors, and has important clinical significance.

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 #

This disclosure relates to compounds useful for degrading BTK via a ubiquitin proteolytic pathway with enhanced IMiD activity. The description also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.

The subject matter described herein relates to compositions comprising Ubiquitin- Specific Protease 1 (USP1) inhibitors and methods of using the same.

The invention belongs to the field of biomedicine, and particularly relates to polypeptide for targeted blocking of combination of TRIM25 and BRD7 protein and application of the polypeptide. According to the present invention, based on the minimum binding region PRYSPRY structural domain (439 aa-630 aa) of the TRIM25 and the BRD7 protein, the blocking peptide TB16 capable of specifically blocking the mutual binding of the TRIM25 and the BRD7 protein is screened, such that the ubiquitination degradation of the BRD7 is inhibited, and the stability of the BRD7 tumor inhibition protein is improved. The polypeptide drug TB16 can effectively inhibit breast cancer, nasopharynx cancer, ovarian cancer, lung cancer and liver cancer cell proliferation and breast cancer in-vivo tumor growth, has good anti-solid tumor activity, and is expected to become a new anti-tumor targeting drug.

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 present invention relates to a new human cereblon (CRBN) E3 ubiquitin ligase inhibitor, which can be used for preparing PROTAC molecules. The CRBN E3 ubiquitin ligase inhibitor and the PROTAC molecules can be used for treating cancer and other diseases.

The invention belongs to the field of gene engineering, and discloses a sucrose isomerase mutant, a high-yield isomaltulose engineering bacterium and a construction method and application thereof. According to the sucrose isomerase mutant obtained through rational design of an enzyme molecular structure, the enzyme activity and the isomaltulose conversion rate of the sucrose isomerase mutant are remarkably improved, compared with a wild enzyme, the specific enzyme activity of the sucrose isomerase mutant is improved by 2.29 times, the isomaltulose conversion rate is improved to 98.9% from 91.1%, the impurity content is lower, and therefore the sucrose isomerase mutant is more suitable for synthesis of isomaltulose. A recombinant engineering bacterium of the high-yield isomaltulose engineering bacterium is further constructed; the recombinant engineering bacterium capable of efficiently expressing the sucrose isomerase is constructed by utilizing ubiquitin-like protein modified molecular genes to be fused with sucrose isomerase mutant coding genes, the enzyme activity of the prepared sucrose isomerase can reach 40.5 U / mg wet cells, and the recombinant engineering bacterium has a great application prospect in industrial production.

The invention provides a protein degradation targeting chimera based on G-quadruplex RNA (Ribonucleic Acid) as well as a preparation method and application of the protein degradation targeting chimera. The structural general formula of the protein degradation targeting chimera is G-L-E, wherein G is G quadruplex RNA specifically combined with mammal fragile X hypophrenia protein (FMRP), E is a ligand of micromolecule E3 ubiquitination ligase, and L is a connecting arm between the G quadruplex RNA and the ligand of the micromolecule E3 ubiquitination ligase. The protein degradation targeting chimera provided by the invention has the advantages that the stability in an in-vivo environment and the capability of entering cells are greatly improved, and the protein degradation targeting chimera also has the capabilities of efficiently degrading FMRP and changing a secretion mode of cancer cells, so that a lot of convenience is provided for the development of nucleic acid PROTAC drugs.

The invention discloses a method for screening breast cancer biomarkers based on weighted gene co-expression network analysis and application. High-expression keratin KRT5 and low-expression ubiquitin coupling enzyme UBE2C in breast cancer patients are screened out and are closely related to good prognosis of the high-expression keratin KRT5 and the low-expression ubiquitin coupling enzyme UBE2C, and the KRT5 and the UBE2C are effective molecular markers for breast cancer early-stage diagnosis and prognosis analysis. In-vitro experiments show that the development process of the breast cancer can be effectively inhibited by promoting the expression of the KRT5 gene and inhibiting the expression of the UBE2C gene. According to the invention, early-stage diagnosis and prognosis analysis of breast cancer can be rapidly carried out, a new direction is provided for diagnosis, treatment and prognosis of breast cancer, and development of individualized treatment is promoted.

Provided herein are certain heteroaromatic compounds, such as a compound of Formula (I), as ubiquitin-specific-processing protease 1 (USP1) inhibitors, pharmaceutical compositions comprising the compounds, and method of use of the compounds or pharmaceutical compositions in the treatment of diseases or disorders.

The invention discloses a high-throughput screening method and a high-throughput screening system for a KLHL24 ubiquitin ligase inhibitor, which are high in stability and good in repeatability and are beneficial to efficient screening of the KLHL24 ubiquitin ligase inhibitor and development of related drugs. Based on the method, some KLHL24 ubiquitin ligase inhibitors are screened out, can be effectively used for treating diseases related to KLHL24, especially diseases caused by KLHL24 mutation, such as hereditary bullous epidermis, dilated cardiomyopathy, alopecia and atrophic scar, and have very good application prospects. In view of the function of KLHL24 in the aspect of skin and hair regeneration, the inhibitor also has a relatively good application prospect in the aspect of maintaining normal hair.

The present invention concerns inhibitors of ubiquitin specific protease 7 (USP7), and methods of use thereof. Specifically, the invention provides compounds according to formula (I), including stereoisomers, pharmaceutically acceptable salt or solvate thereof:

Small molecule inhibitory compounds of ubiquitin-specific protease 1 (USP1) and compositions comprising the same are provided. Also provided are methods for targeting ubiquitin-specific protease 1 (USP1) and methods of treating diseases or disorders associated with USP1, such as cancer.

Disclosed are a pyrimidine compound, a preparation method therefor and a medical use thereof. Specifically, disclosed are a compound represented by the general formula (SI), a preparation method therefor, a pharmaceutical composition containing said compound, and a use thereof as a ubiquitin-specific protease 1 (USP1) inhibitor, particularly a use thereof for treating or preventing cancer. The definitions of the groups in the general formula (SI) are the same as those in the description.

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.

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 presently disclosed subject matter relates to compositions comprising Ubiquitin-Specific Protease 1 (USP1) inhibitors and methods of using the same.

The present disclosure relates, at least in part, to methods and cells useful for promoting ubiquitination-independent protein degradation and for promoting protein stability using an engineered midnolin protein.

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.

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 invention belongs to the field of biological medicines, and relates to application of a pharmaceutical preparation containing BAY 73-6691 or a derivative thereof in preparation of a medicine for treating brain injury diseases. Wherein the structural formula of the BAY 73-6691 is as follows: # imgabs0 #. The pharmaceutical preparation comprises the BAY 73 to 6691 and / or a pharmaceutically acceptable salt of the BAY 73 to 6691. According to the present invention, the research results show that the BAY 73-6691 can improve the ARCA brain injury through the ubiquitin phosphorylation dual pathway, such that the BAY 73-6691 may become the ARCA treatment candidate drug; the application further explains a new drug mechanism and an action target spot of the BAY 73-6691; meanwhile, a new supplement is expected to be provided in clinical application of new use of old medicines.

Provided herein are complexes, methods, and therapeutic uses for inducing and / or enhancing the ubiquitination of proteins such as NRF2 by beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC).

The invention relates to the technical field of medicines, in particular to a substituted trifused ring ubiquitin specific protease 1 (USP1) inhibitor compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, a pharmaceutical composition containing the compound, the pharmaceutically acceptable salt thereof, or the stereoisomer thereof, and a preparation containing the compound, the pharmaceutically acceptable salt thereof, or the stereoisomer thereof. The invention relates to a compound, a pharmaceutically acceptable salt or a stereoisomer thereof, a method for preparing the compound, the pharmaceutically acceptable salt or the stereoisomer thereof, and application of the compound, the pharmaceutically acceptable salt or the stereoisomer thereof in preparation of drugs for treating and / or preventing USPl-mediated diseases and related diseases.

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.

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 invention discloses application of ubiquitin specific protease USP4 in treatment of acute lung injury / acute respiratory distress syndrome. The GEO database analysis finds that USP4 is increased in patients with acute respiratory distress syndrome; the expression level of USP4 is increased by stimulating human neutrophils in vitro with LPS, and experiments prove that the USP4 inhibitor Vialinin A can effectively treat acute lung injury and effectively improve the survival rate of mice; acute lung injury can be effectively relieved by using adenovirus to inhibit expression of USP4 in lung; the USP4 defect of the hematopoietic system can effectively relieve acute lung injury. The application of the USP4 serving as the target spot in screening the medicine for treating the acute lung injury or the acute respiratory distress syndrome is provided for the first time, a new target spot is provided for treating the acute lung injury or the acute respiratory distress syndrome, and a new treatment strategy is provided for clinical treatment.

The present invention relates to oligonucleotides that are capable of inducing expression of ubiquitin-protein ligase E3A (UBE3A) from the paternal allele in animal or human neurons. The oligonucleotides target the suppressor of the UBE3A paternal allele by hybridization to SNHG14 long non-coding RNA downstream of SNORD109B. The present invention further relates to pharmaceutical compositions and methods for treatment of Angelman syndrome.

The invention relates to a difunctional chimera heterocyclic compound for targeted degradation of an androgen receptor and application of the difunctional chimera heterocyclic compound, and particularly provides a compound shown in a formula (I), or an isotope compound of the compound, or an optical isomer of the compound, or a tautomer of the compound, or a pharmaceutically acceptable salt of the compound, or a prodrug of the compound, or a solvate of the compound, aRB is an androgen receptor recognition / combination part, L is a linking part, and U is a ubiquitin protease recognition / combination part; the three parts are connected through chemical bonds. The compound provided by the invention can degrade androgen receptors in prostate cancer cells in a targeted manner and inhibit proliferation of the prostate cancer cells, and also shows good metabolic stability and pharmacokinetic properties. The compound provided by the invention has a good application prospect in preparation of a protein degradation targeting chimera of an androgen receptor and in preparation of drugs for treating related diseases (including prostatic cancer, breast cancer and Kenildie disease) regulated and controlled by the androgen receptor. # imgabs0 #

Provided are: a compound defined by chemical formula 1; a stereoisomer thereof; a tautomer thereof; and pharmaceutically acceptable salts of the compound, the stereoisomer, and the tautomer. The compound according to the present invention can inhibit the activity of the USP1 enzyme. In chemical formula 1, R1 to R4 and [the symbol A in chemical formula 1] are as defined in the present specification.