Leveraging Compound Promiscuity to Identify Targetable Cysteines within the Kinome

Suman Rao, Deepak Gurbani, Guangyan Du, Robert A. Everley, Christopher M. Browne, Apirat Chaikuad, Li Tan, Martin Schröder, Sudershan Gondi, Scott B. Ficarro, Taebo Sim, Nam Doo Kim, Matthew J. Berberich, Stefan Knapp, Jarrod A. Marto, Kenneth D. Westover, Peter K. Sorger, Nathanael S. Gray

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)


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. The current work by Rao et al. describes using a promiscuous ligand as a tool to identify new targets for drug discovery. The findings from this study highlight previously unknown targets against which irreversible inhibitors can be developed. These targets are typically deregulated in diseases including cancer.

Original languageEnglish
Pages (from-to)818-829.e9
JournalCell Chemical Biology
Issue number6
Publication statusPublished - 2019 Jun 20


  • chemical probe
  • chemoproteomics
  • covalent inhibitors
  • crystal structure
  • cysteines
  • drug discovery
  • kinase inhibitors
  • kinobeads
  • multi-targeted compounds
  • target engagement

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry


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