Rao, Suman Gurbani, Deepak Du, Guangyan Everley, Robert A. Browne, Christopher M. Chaikuad, Apirat Tan, Li Schroeder, Martin Gondi, Sudershan Ficarro, Scott B. Sim, Taebo Kim, Nam Doo Berberich, Matthew J. Knapp, Stefan Marto, Jarrod A. Westover, Kenneth D. Sorger, Peter K. Gray, Nathanael S. 2024-01-19T20:00:57Z 2024-01-19T20:00:57Z 2022-01-25 2019-06 2451-9448 https://pubs.kist.re.kr/handle/201004/119902 Covalent kinase inhibitors, which typically target cysteine residues, represent an important class of clinically relevant compounds. Approximately 215 kinases are known to have potentially targetable cysteines distributed across 18 spatially distinct locations proximal to the ATP-binding pocket. However, only 40 kinases have been covalently targeted, with certain cysteine sites being the primary focus. To address this disparity, we have developed a strategy that combines the use of a multi-targeted acrylamide-modified inhibitor, SM1-71, with a suite of complementary chemoproteomic and cellular approaches to identify additional targetable cysteines. Using this single multi-targeted compound, we successfully identified 23 kinases that are amenable to covalent inhibition including MKNK2, MAP2K1/2/3/4/ 6/7, GAK, AAK1, BMP2K, MAP3K7, MAPKAPK5, GSK3A/B, MAPK1/3, SRC, YES1, FGFR1, ZAK (MLTK), MAP3K1, LIMK1, and RSK2. The identification of nine of these kinases previously not targeted by a covalent inhibitor increases the number of targetable kinases and highlights opportunities for covalent kinase inhibitor development. English CELL PRESS Leveraging Compound Promiscuity to Identify Targetable Cysteines within the Kinome Article 10.1016/j.chembiol.2019.02.021 1 CELL CHEMICAL BIOLOGY, v.26, no.6, pp.818 - + CELL CHEMICAL BIOLOGY 26 6 818 + N scie scopus 000472159700005 2-s2.0-85067237871 Biochemistry & Molecular Biology Biochemistry & Molecular Biology Article IRREVERSIBLE INHIBITORS COVALENT INHIBITORS KINASE INHIBITORS BINDING 1ST IDENTIFICATION DISCOVERY SRC EXPRESSION REACTIVITY chemical probe chemoproteomics covalent inhibitors crystal structure cysteines drug discovery kinase inhibitors kinobeads multi-targeted compounds target engagement