Selective and Potent PROTAC Degraders of c-Src Kinase.

Autor: Mao W; Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, Michigan 48109, United States., Vandecan NM; Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, Michigan 48109, United States., Bingham CR; Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, Michigan 48109, United States., Tsang PK; Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, Michigan 48109, United States., Ulintz P; Department of Internal Medicine, University of Michigan, 1500 E. Medical Avenue, Ann Arbor, Michigan 48109, United States., Sexton R; Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, Michigan 48109, United States., Bochar DA; Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, Michigan 48109, United States., Merajver SD; Department of Internal Medicine, University of Michigan, 1500 E. Medical Avenue, Ann Arbor, Michigan 48109, United States., Soellner MB; Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, Michigan 48109, United States.; Department of Internal Medicine, University of Michigan, 1500 E. Medical Avenue, Ann Arbor, Michigan 48109, United States.
Jazyk: angličtina
Zdroj: ACS chemical biology [ACS Chem Biol] 2024 Jan 19; Vol. 19 (1), pp. 110-116. Date of Electronic Publication: 2023 Dec 19.
DOI: 10.1021/acschembio.3c00548
Abstrakt: Using dasatinib linked to E3 ligase ligands, we identified a potent and selective dual Csk/c-Src PROTAC degrader. We then replaced dasatinib, the c-Src-directed ligand, with a conformation-selective analogue that stabilizes the αC-helix-out conformation of c-Src. Using the αC-helix-out ligand, we identified a PROTAC that is potent and selective for c-Src. We demonstrated a high degree of catalysis with our c-Src PROTACs. Using our c-Src PROTACs, we identified pharmacological advantages of c-Src degradation compared to inhibition with respect to cancer cell proliferation.
Databáze: MEDLINE
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