دورية أكاديمية
Chemical Specification of E3 Ubiquitin Ligase Engagement by Cysteine-Reactive Chemistry.
| العنوان: | Chemical Specification of E3 Ubiquitin Ligase Engagement by Cysteine-Reactive Chemistry. |
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| المؤلفون: | Sarott RC; Department of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, California 94305, United States., You I; Department of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, California 94305, United States., Li YD; Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, United States.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02141, United States., Toenjes ST; Department of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, California 94305, United States., Donovan KA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States., Seo P; Department of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, California 94305, United States., Ordonez M; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.; Department of Pediatrics, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Harvard University, Boston, Massachusetts 02215, United States., Byun WS; Department of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, California 94305, United States., Hassan MM; Department of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, California 94305, United States., Wachter F; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States.; Department of Pediatrics, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Harvard University, Boston, Massachusetts 02215, United States., Chouchani ET; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, United States., Słabicki M; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02141, United States., Fischer ES; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States., Ebert BL; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02141, United States.; Howard Hughes Medical Institute, Boston, Massachusetts 02115, United States., Hinshaw SM; Department of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, California 94305, United States., Gray NS; Department of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, California 94305, United States. |
| المصدر: | Journal of the American Chemical Society [J Am Chem Soc] 2023 Oct 11; Vol. 145 (40), pp. 21937-21944. Date of Electronic Publication: 2023 Sep 28. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 7503056 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-5126 (Electronic) Linking ISSN: 00027863 NLM ISO Abbreviation: J Am Chem Soc Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington, DC : American Chemical Society Original Publication: Easton, Pa. [etc.] |
| مستخلص: | Targeted protein degradation relies on small molecules that induce new protein-protein interactions between targets and the cellular protein degradation machinery. Most of these small molecules feature specific ligands for ubiquitin ligases. Recently, the attachment of cysteine-reactive chemical groups to pre-existing small molecule inhibitors has been shown to drive specific target degradation. We demonstrate here that different cysteine-reactive groups can specify target degradation via distinct ubiquitin ligases. By focusing on the bromodomain ligand JQ1, we identify cysteine-reactive functional groups that drive BRD4 degradation by either DCAF16 or DCAF11. Unlike proteolysis-targeting chimeric molecules (PROTACs), the new compounds use a single small molecule ligand with a well-positioned cysteine-reactive group to induce protein degradation. The finding that nearly identical compounds can engage multiple ubiquitination pathways suggests that targeting cellular pathways that search for and eliminate chemically reactive proteins is a feasible avenue for converting existing small molecule drugs into protein degrader molecules. |
| تواريخ الأحداث: | Date Created: 20230928 Latest Revision: 20231011 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1021/jacs.3c06622 |
| PMID: | 37767920 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-5126 |
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| DOI: | 10.1021/jacs.3c06622 |