Fragment-Based Discovery and Structure-Guided Optimization of 2-Benzoyl-7-azabenzimidazoles as Potent, Highly Selective and Orally Active CDK4/6 Inhibitors

Herein we describe the discovery of potent and highly selective inhibitors of both CDK4 and CDK6 via structure-guided optimization of a fragment-based screening hit. CDK6 X-ray crystallography and pharmacokinetic data steered efforts in identifying compound 10 which showed >1000-fold selectivity for CDK4/6 over CDKs 1 and 2 in an enzymatic assay. Furthermore, compound 10 demonstrated in vivo inhibition of pRb-phosphorylation and oral efficacy in a Jeko-1 mouse xenograft model.