دورية أكاديمية
Discovery of Selective Small Molecule Degraders of BRAF-V600E.
| العنوان: | Discovery of Selective Small Molecule Degraders of BRAF-V600E. |
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| المؤلفون: | Han XR; Cullgen Inc., 12671 High Bluff Drive, Suite 130, San Diego, California 92130, United States.; Cullgen (Shanghai) Inc., Building 6, 230 ChuanHong Road, Chuansha, Pudong New Area, Shanghai 201202, People's Republic of China., Chen L; Cullgen (Shanghai) Inc., Building 6, 230 ChuanHong Road, Chuansha, Pudong New Area, Shanghai 201202, People's Republic of China., Wei Y; Cullgen (Shanghai) Inc., Building 6, 230 ChuanHong Road, Chuansha, Pudong New Area, Shanghai 201202, People's Republic of China., Yu W; Cullgen (Shanghai) Inc., Building 6, 230 ChuanHong Road, Chuansha, Pudong New Area, Shanghai 201202, People's Republic of China., Chen Y; Cullgen (Shanghai) Inc., Building 6, 230 ChuanHong Road, Chuansha, Pudong New Area, Shanghai 201202, People's Republic of China., Zhang C; Cullgen (Shanghai) Inc., Building 6, 230 ChuanHong Road, Chuansha, Pudong New Area, Shanghai 201202, People's Republic of China., Jiao B; Cullgen (Shanghai) Inc., Building 6, 230 ChuanHong Road, Chuansha, Pudong New Area, Shanghai 201202, People's Republic of China., Shi T; Cullgen (Shanghai) Inc., Building 6, 230 ChuanHong Road, Chuansha, Pudong New Area, Shanghai 201202, People's Republic of China., Sun L; Cullgen (Shanghai) Inc., Building 6, 230 ChuanHong Road, Chuansha, Pudong New Area, Shanghai 201202, People's Republic of China., Zhang C; Cullgen (Shanghai) Inc., Building 6, 230 ChuanHong Road, Chuansha, Pudong New Area, Shanghai 201202, People's Republic of China., Xu Y; Cullgen (Shanghai) Inc., Building 6, 230 ChuanHong Road, Chuansha, Pudong New Area, Shanghai 201202, People's Republic of China., Lee MR; Cullgen Inc., 12671 High Bluff Drive, Suite 130, San Diego, California 92130, United States., Luo Y; Cullgen Inc., 12671 High Bluff Drive, Suite 130, San Diego, California 92130, United States., Plewe MB; Cullgen Inc., 12671 High Bluff Drive, Suite 130, San Diego, California 92130, United States., Wang J; Cullgen Inc., 12671 High Bluff Drive, Suite 130, San Diego, California 92130, United States.; Cullgen (Shanghai) Inc., Building 6, 230 ChuanHong Road, Chuansha, Pudong New Area, Shanghai 201202, People's Republic of China. |
| المصدر: | Journal of medicinal chemistry [J Med Chem] 2020 Apr 23; Vol. 63 (8), pp. 4069-4080. Date of Electronic Publication: 2020 Apr 10. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| 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: | Drug Discovery/*methods , Protein Kinase Inhibitors/*chemistry , Protein Kinase Inhibitors/*metabolism , Proteolysis/*drug effects , Proto-Oncogene Proteins B-raf/*metabolism, Cell Survival/drug effects ; Cell Survival/physiology ; Dose-Response Relationship, Drug ; Humans ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins B-raf/antagonists & inhibitors ; Vemurafenib/chemistry ; Vemurafenib/metabolism ; Vemurafenib/pharmacology |
| مستخلص: | BRAF is among the most frequently mutated oncogenes in human cancers. Multiple small molecule BRAF kinase inhibitors have been approved for treating melanoma carrying BRAF-V600 mutations. However, the benefits of BRAF kinase inhibitors are generally short-lived. Small molecule-mediated targeted protein degradation has recently emerged as a novel pharmaceutical strategy to remove disease proteins through hijacking the cellular ubiquitin proteasome system (UPS). In this study, we developed thalidomide-based heterobifunctional compounds that induced selective degradation of BRAF-V600E, but not the wild-type BRAF. Downregulation of BRAF-V600E suppressed the MEK/ERK kinase cascade in melanoma cells and impaired cell growth in culture. Abolishing the interaction between degraders and cereblon or blocking the UPS significantly impaired the activities of these degraders, validating a mechanistic role of UPS in mediating targeted degradation of BRAF-V600E. These findings highlight a new approach to modulate the functions of oncogenic BRAF mutants and provide a framework to treat BRAF-dependent human cancers. |
| المشرفين على المادة: | 0 (Protein Kinase Inhibitors) 207SMY3FQT (Vemurafenib) EC 2.7.11.1 (BRAF protein, human) EC 2.7.11.1 (Proto-Oncogene Proteins B-raf) |
| تواريخ الأحداث: | Date Created: 20200401 Date Completed: 20200924 Latest Revision: 20200924 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1021/acs.jmedchem.9b02083 |
| PMID: | 32223235 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-4804 |
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| DOI: | 10.1021/acs.jmedchem.9b02083 |