Discovery of potent and selective CDK8 inhibitors through FBDD approach.

A fragment library screen was carried out to identify starting points for novel CDK8 inhibitors. Optimization of a fragment hit guided by co-crystal structures led to identification of a novel series of potent CDK8 inhibitors which are highly ligand efficient, kinase selective and cellular active. Compound 16 was progressed to a mouse pharmacokinetic study and showed good oral bioavailability.