Design and Development of a Series of Potent and Selective Type II Inhibitors of CDK8

  • ACS Med Chem Lett. 2016 Apr 5;7(6):595-600. doi: 10.1021/acsmedchemlett.6b00044.
Philippe Bergeron  1 ,  Michael F T Koehler  1 ,  Elizabeth M Blackwood  1 ,  Krista Bowman  1 ,  Kevin Clark  1 ,  Ron Firestein  1 ,  James R Kiefer  1 ,  Klaus Maskos  2 ,  Mark L McCleland  1 ,  Linda Orren  1 ,  Sreemathy Ramaswamy  1 ,  Laurent Salphati  1 ,  Steve Schmidt  1 ,  Elisabeth V Schneider  3 ,  Jiansheng Wu  1 ,  Maureen Beresini  1
Affiliations
  • 1. Department of Discovery Chemistry, Department of Translational Oncology, Department of Structural Biology, Department of Small Molecule Biochemical Pharmacology, Department of Pathology, Department of Drug Metabolism, and Department of Protein Chemistry, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
  • 2. Proteros Biostructures GmbH , Bunsenstr. 7a, D-82152 Martinsried, Germany.
  • 3. Proteros Biostructures GmbH, Bunsenstr. 7a, D-82152 Martinsried, Germany; Max-Planck-Institut für Biochemie, Am Klopferspitz 18a, D-82152 Martinsried, Germany.
PMID: 27326333 DOI: 10.1021/acsmedchemlett.6b00044
Abstract

Using Sorafenib as a starting point, a series of potent and selective inhibitors of CDK8 was developed. When cocrystallized with CDK8 and cyclin C, these compounds exhibit a Type-II (DMG-out) binding mode.

Keywords
CDK8; DMG-out; Sorafenib; inhibitor.