A multi-targeted probe-based strategy to identify signaling vulnerabilities in cancers
Suman Rao,1,2,3 Deepak Gurbani,4 Guangyan Du,2,3 Robert A. Everley,1 Christopher M. Browne,2,3,5 Apirat Chaikuad,6,7 Li Tan,2,3 Martin Schroder,6,7 Sudershan Gondi,4 Scott B. Ficarro,2,3,5 Taebo Sim,8,9 Nam Doo Kim,10 Matthew J. Berberich,1 Stefan Knapp,6,7,11 Jarrod A. Marto,2,3,5 Kenneth D. Westover,4 Peter K. Sorger,1,* and Nathanael S. Gray2,3,12,*
1Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA; 2Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; 3Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; 4Departments of Biochemistry and Radiation Oncology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA; 5Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA; 6Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, 60438 Frankfurt am Main, Germany; 7Buchmann Institute for Life Sciences and Structural Genomics Consortium Goethe-University Frankfurt, 60438 Frankfurt am Main, Germany; 8Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea; 9KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea; 10NDBio Therapeutics Inc., Incheon 21984, Republic of Korea; 11German Cancer Network, Frankfurt Site, 60438 Frankfurt am Main, Germany; 12Lead Contact
Cell Chemical Biology (2019) 26, 818–829. doi:10.1016/j.chembiol.2019.02.021
Deregulation of kinase proteins alters cellular signaling and can result in diverse diseases including cancer. The majority of recently approved kinase inhibitor cancer drugs work by reversibly binding kinases. While covalent kinase inhibitors that irreversibly bind and inhibit these proteins are potentially more effective as therapeutic agents, only a fraction of the kinome has been covalently targeted. Rao et al. describe using a multi-target chemical probe to scan kinases for potential sites of covalent bonding to identify 23 new targets for drug discovery.
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.
This work was supported by grants Welch I-1829 (to K.D.W), CPRIT RP140233 (to K.D.W.), P50-GM107618, U54HL127365, U54-CA225088, and KU-KIST Graduate School of Converging Science and Technology Program. S.R. was supported by a Jonathan M. Goldstein and Kaia Miller Goldstein Systems Pharmacology Fellowship.
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