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ACS Med Chem Lett. 2016 Jan 6;7(3):223-8. doi: 10.1021/acsmedchemlett.5b00278. eCollection 2016 Mar 10.

Development of a Potent, Specific CDK8 Kinase Inhibitor Which Phenocopies CDK8/19 Knockout Cells.

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Departments of Discovery Chemistry, Translational Oncology, Structural Biology, Biochemical and Cellular Pharmacology, Pathology, Drug Metabolism and Pharmacokinetics, and Structural Biology, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
Proteros Biostructures GmbH , Bunsenstr. 7a, D-82152 Martinsried, Germany.
Proteros Biostructures GmbH, Bunsenstr. 7a, D-82152 Martinsried, Germany; Max-Planck-Institut für Biochemie, Am Klopferspitz 18a, D-82152 Martinsried, Germany.


Beginning with promiscuous COT inhibitors, which were found to inhibit CDK8, a series of 6-aza-benzothiophene containing compounds were developed into potent, selective CDK8 inhibitors. When cocrystallized with CDK8 and cyclin C, these compounds exhibit an unusual binding mode, making a single hydrogen bond to the hinge residue A100, a second to K252, and a key cation-π interaction with R356. Structure-based drug design resulted in tool compounds 13 and 32, which are highly potent, kinase selective, permeable compounds with a free fraction >2% and no measurable efflux. Despite these attractive properties, these compounds exhibit weak antiproliferative activity in the HCT-116 colon cancer cell line. Further examination of the activity of 32 in this cell line revealed that the compound reduced phosphorylation of the known CDK8 substrate STAT1 in a manner identical to a CDK8 knockout clone, illustrating the complex effects of inhibition of CDK8 kinase activity in proliferation in these cells.


CDK8; cyclin C; kinase inhibitor

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