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

Philippe Bergeron; Michael F T Koehler; Elizabeth M Blackwood; Krista Bowman; Kevin Clark; Ron Firestein; James R Kiefer; Klaus Maskos; Mark L McCleland; Linda Orren; Sreemathy Ramaswamy; Laurent Salphati; Steve Schmidt; Elisabeth V Schneider; Jiansheng Wu; Maureen Beresini

doi:10.1021/acsmedchemlett.6b00044

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. eCollection 2016 Jun 9.

Authors

Philippe Bergeron¹, Michael F T Koehler¹, Elizabeth M Blackwood¹, Krista Bowman¹, Kevin Clark¹, Ron Firestein¹, James R Kiefer¹, Klaus Maskos², Mark L McCleland¹, Linda Orren¹, Sreemathy Ramaswamy¹, Laurent Salphati¹, Steve Schmidt¹, Elisabeth V Schneider³, Jiansheng Wu¹, Maureen Beresini¹

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.

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.