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

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.