دورية أكاديمية
Discovery of Potent and Selective c-Met Degraders for Hepatocellular Carcinoma Treatment.
| العنوان: | Discovery of Potent and Selective c-Met Degraders for Hepatocellular Carcinoma Treatment. |
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| المؤلفون: | Min W; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China., Yang H; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China., Wang D; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China., Chen C; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China., Wang Y; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China., Hou Y; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China., Zhu Y; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China., Sun C; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China., Wang X; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China., Yuan K; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China., Yang P; State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.; Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China. |
| المصدر: | Journal of medicinal chemistry [J Med Chem] 2024 Jul 25; Vol. 67 (14), pp. 12314-12330. Date of Electronic Publication: 2024 Jul 04. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington Dc : American Chemical Society Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
| مواضيع طبية MeSH: | Proto-Oncogene Proteins c-met*/antagonists & inhibitors , Proto-Oncogene Proteins c-met*/metabolism , Carcinoma, Hepatocellular*/drug therapy , Carcinoma, Hepatocellular*/pathology , Carcinoma, Hepatocellular*/metabolism , Liver Neoplasms*/drug therapy , Liver Neoplasms*/pathology , Liver Neoplasms*/metabolism , Antineoplastic Agents*/pharmacology , Antineoplastic Agents*/chemistry , Antineoplastic Agents*/chemical synthesis , Antineoplastic Agents*/therapeutic use, Humans ; Cell Line, Tumor ; Structure-Activity Relationship ; Animals ; Cell Proliferation/drug effects ; Drug Discovery ; Proteolysis/drug effects ; Drug Screening Assays, Antitumor ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/chemical synthesis ; Protein Kinase Inhibitors/therapeutic use ; Mice |
| مستخلص: | Targeting c-Met is a clinical trend for the precise treatment of HCC, but the potential issue of acquired drug resistance cannot be ignored. Targeted protein degradation technology has demonstrated promising prospects in disease treatment and overcoming drug resistance due to its special mechanism of action. In this study, we designed and synthesized two series of novel c-Met degraders and conducted a systematic biological evaluation of the optimal compound H11 . H11 exhibited good c-Met degradation activity and anti-HCC activity. Importantly, H11 also demonstrated more potent inhibitory activity against Ba/F3-TPR-MET-D1228N and Ba/F3-TPR-MET-Y1230H cell lines than did tepotinib. In summary, H11 displayed potent anti-HCC activity as a degrader and may overcome resistance to type Ib inhibitors, making it a new therapeutic strategy for HCC with MET alterations. |
| المشرفين على المادة: | EC 2.7.10.1 (Proto-Oncogene Proteins c-met) 0 (Antineoplastic Agents) EC 2.7.10.1 (MET protein, human) 0 (Protein Kinase Inhibitors) |
| تواريخ الأحداث: | Date Created: 20240704 Date Completed: 20240725 Latest Revision: 20240729 |
| رمز التحديث: | 20240730 |
| DOI: | 10.1021/acs.jmedchem.4c01004 |
| PMID: | 38962837 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-4804 |
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| DOI: | 10.1021/acs.jmedchem.4c01004 |