2. Academic Validation
  3. Leveraging Compound Promiscuity to Identify Targetable Cysteines within the Kinome

Leveraging Compound Promiscuity to Identify Targetable Cysteines within the Kinome

  • Cell Chem Biol. 2019 Jun 20;26(6):818-829.e9. doi: 10.1016/j.chembiol.2019.02.021.
Suman Rao 1,  Deepak Gurbani 2,  Guangyan Du 3,  Robert A Everley 4,  Christopher M Browne 5,  Apirat Chaikuad 6,  Li Tan 3,  Martin Schröder 6,  Sudershan Gondi 2,  Scott B Ficarro 5,  Taebo Sim 7,  Nam Doo Kim 8,  Matthew J Berberich 4,  Stefan Knapp 9,  Jarrod A Marto 5,  Kenneth D Westover 2,  Peter K Sorger 10,  Nathanael S Gray 11
Affiliations

Affiliations

  • 1 Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • 2 Departments of Biochemistry and Radiation Oncology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
  • 3 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • 4 Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • 5 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • 6 Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max von Lauestr. 9, 60438 Frankfurt am Main, Germany; Buchmann Institute for Life Sciences (BMLS) and Structural Genomics Consortium Goethe-University Frankfurt, Max von Lauestr. 9, 60438 Frankfurt am Main, Germany.
  • 7 Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), 5 Hwarangro 14-gil, Seongbuk-gu, Seoul 02792, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea.
  • 8 NDBio Therapeutics Inc., Incheon 21984, Republic of Korea.
  • 9 Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max von Lauestr. 9, 60438 Frankfurt am Main, Germany; Buchmann Institute for Life Sciences (BMLS) and Structural Genomics Consortium Goethe-University Frankfurt, Max von Lauestr. 9, 60438 Frankfurt am Main, Germany; German Cancer Network (DKTK), Frankfurt Site, 60438 Frankfurt am Main, Germany.
  • 10 Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: peter_sorger@hms.harvard.edu.
  • 11 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: nathanael_gray@dfci.harvard.edu.
PMID: 30982749 DOI: 10.1016/j.chembiol.2019.02.021
Abstract

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.

Keywords

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

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