Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19

作者：Mallinger Aurelie; Schiemann Kai; Rink Christian; Stieber Frank; Calderini Michel; Crumpler Simon; Stubbs Mark; Adeniji Popoola Olajumoke; Poeschke Oliver; Busch Michael; Czodrowski Paul; Musil Djordje; Schwarz Daniel; Ortiz Ruiz Maria Jesus; Schneider Richard; Thai Ching; Valenti Melanie; Brandon Alexis de Haven; Burke Rosemary; Workman Paul; Dale Trevor; Wienke Dirk; Clarke Paul A; Esdar Christina; Raynaud Florence I; Eccles Suzanne A; Rohdich Felix

来源：Journal of Medicinal Chemistry, 2016, 59(3): 1078-1101.

DOI：10.1021/acs.jmedchem.5b01685

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.

• 出版日期2016-2-11