Studies of CDK 8/19 inhibitors: Discovery of novel and selective CDK8/19 dual inhibitors and elimination of their CYP3A4 time-dependent inhibition potential

Abstract In this article, synthetic studies around a pyridylacrylamide-based hit compound ( 1 ), utilizing structure-based drug designguided by CDK8 docking models, is discussed. Modification of the pendant 4-fluorophenyl group to various heteroaromatic rings was conducted aiming an interaction with the proximal amino acids, and then replacement of the morpholinering was targeted for decreasing potential of time-dependent CYP3A4inhibition. These efforts led to the compound 4k , with enhanced CDK8 inhibitory activity and no apparent potential for time-dependent CYP3A4inhibition (CDK8 IC 50 : 2.5 nM; CYP3A4TDI: 99% compound remaining). Compound 4k was found to possess a highly selective kinase inhibition profile, and also showed favorable pharmacokinetic profile. Oral administration of 4k (15 mg/kg, bid. for 2 weeks) suppressed tumor growth (T/C 29%) in an RPMI8226 mouse xenograft model.