The Mediator complex-associated kinase CDK8 has been implicated in human disease,1 particularly in colorectal cancer where CDK8 has been reported as a putative oncogene.2 We previously reported the discovery of CCT251545, a potent, orally bioavailable small molecule inhibitor of Wnt signalling from a cell-based pathway screen.3 We identified protein kinase paralogs CDK8 and CDK19 as the primary targets of this chemical series.4 Protein X-ray crystallography studies of the chemical probe CCT251545 in complex with CDK8/cyclin C revealed an unusual protein binding conformation invoking a C-terminal loop insertion into the ATP binding site and enabled the design of improved CDK8/19-selective compounds. We optimized the metabolic stability and aqueous solubility of the chemical probe CCT251545 in order to facilitate further in vivo evaluation of CDK8/19 pharmacology and progression into preclinical in vivo studies. Here we describe the medicinal chemistry optimisation of CCT251545 to CCT251921, a potent, highly selective and orally bioavailable dual CDK8/19 ligand with excellent translation to cell-based activity and improved pharmacokinetic and pharmaceutical properties. Demonstration of in vivo activity following oral dosing in solid human tumor xenograft model will also be shown. 1 Porter, D.C. et al. Proc. Natl. Acad. Sci. USA 2012, 109, 13799-13804 2 Firestein, R. et al. Nature 2008, 455, 547-551 3 Mallinger, A. et al. J. Med.Chem. 2015, 58, 1717-1735 4 Dale, T., Clarke, P. A. et al. Nat. Chem. Biol. manuscript in press

Discovery of CCT251921: A potent, selective and orally bioavailable small molecule modulator of the mediator complex-associated kinases CDK8 and CDK19

251st National Meeting (2016)

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