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

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• 作者：Michael F. T. Koehler ; Philippe Bergeron ; Elizabeth M. Blackwood ; Krista Bowman ; Kevin R. Clark ; Ron Firestein ; James R. Kiefer ; Klaus Maskos ; Mark L. McCleland ; Linda Orren ; Laurent Salphati ; Steve Schmidt ; Elisabeth V. Schneider ; Jiansheng Wu ; Maureen H. Beresini
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：March 10, 2016
• 年：2016
• 卷：7
• 期：3
• 页码：223-228
• 全文大小：366K
• ISSN：1948-5875

文摘

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.