Discovery of Covalent CDK14 Inhibitors with Pan-TAIRE Family Specificity

  • Cell Chem Biol. 2019 Jun 20;26(6):804-817.e12. doi: 10.1016/j.chembiol.2019.02.015.
Fleur M Ferguson  1 ,  Zainab M Doctor  1 ,  Scott B Ficarro  2 ,  Christopher M Browne  1 ,  Jarrod A Marto  3 ,  Jared L Johnson  4 ,  Tomer M Yaron  5 ,  Lewis C Cantley  4 ,  Nam Doo Kim  6 ,  Taebo Sim  7 ,  Matthew J Berberich  8 ,  Marian Kalocsay  8 ,  Peter K Sorger  8 ,  Nathanael S Gray  9
Affiliations
  • 1. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
  • 2. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
  • 3. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 4. Meyer Cancer Center, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
  • 5. Meyer Cancer Center, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA; Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA.
  • 6. Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Republic of Korea.
  • 7. Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea.
  • 8. HMS LINCS Center and Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
  • 9. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: [email protected].
PMID: 30930164 DOI: 10.1016/j.chembiol.2019.02.015
Abstract

Cyclin-dependent kinase 14 (CDK14) and Other TAIRE family kinases (CDKs 15-18) are proteins that lack functional annotation but are frequent off-targets of clinical kinase inhibitors. In this study we develop and characterize FMF-04-159-2, a tool compound that specifically targets CDK14 covalently and possesses a TAIRE kinase-biased selectivity profile. This tool compound and its reversible analog were used to characterize the cellular consequences of covalent CDK14 inhibition, including an unbiased investigation using phospho-proteomics. To reduce confounding off-target activity, washout conditions were used to deconvolute CDK14-specific effects. This investigation suggested that CDK14 plays a supporting role in cell-cycle regulation, particularly mitotic progression, and identified putative CDK14 substrates. Together, these results represent an important step forward in understanding the cellular consequences of inhibiting CDK14 kinase activity.

Keywords
CDK14; TAIRE kinase; cell cycle; covalent inhibitor; druggable genome; mitosis.
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