Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19
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- 作者：Aurélie Mallinger ; Kai Schiemann ; Christian Rink ; Frank Stieber ; Michel Calderini ; Simon Crumpler ; Mark Stubbs ; Olajumoke Adeniji-Popoola ; Oliver Poeschke ; Michael Busch ; Paul Czodrowski ; Djordje Musil ; Daniel Schwarz ; Maria-Jesus Ortiz-Ruiz ; Richard Schneider ; Ching Thai ; Melanie Valenti ; Alexis de Haven Brandon ; Rosemary Burke ; Paul Workman ; Trevor Dale ; Dirk Wienke ; Paul A. Clarke ; Christina Esdar ; Florence I. Raynaud ; Suzanne A. Eccles ; Felix Rohdich ; Julian Blagg
- 刊名：Journal of Medicinal Chemistry
- 出版年：2016
- 出版时间：February 11, 2016
- 年：2016
- 卷：59
- 期：3
- 页码：1078-1101
- 全文大小：1243K
- ISSN：1520-4804
文摘
The Mediator complex-associated cyclin-dependent kinase CDK8 has been implicated in human disease, particularly in colorectal cancer where it has been reported as a putative oncogene. Here we report the discovery of 109 (CCT251921), a potent, selective, and orally bioavailable inhibitor of CDK8 with equipotent affinity for CDK19. We describe a structure-based design approach leading to the discovery of a 3,4,5-trisubstituted-2-aminopyridine series and present the application of physicochemical property analyses to successfully reduce in vivo metabolic clearance, minimize transporter-mediated biliary elimination while maintaining acceptable aqueous solubility. Compound 109 affords the optimal compromise of in vitro biochemical, pharmacokinetic, and physicochemical properties and is suitable for progression to animal models of cancer.