Discovery of a Potent Dual Target CDK8 and Cyclic C PROTAC Degrader for Treatment of Colorectal Cancer

Abstract

CDK8 exerts important physiological functions, particularly in CRC, by forming intermediate complexes with Cyclic C, MED12, and MED13. In this work, different from the design of traditional single CDK8 protac degraders, a novel potent dual target CDK8 and Cyclic C protac degrader (compound 3) were designed and synthesized. It exhibited the good degradation efficiency against CDK8 ((DC 50 =2.58 μM) and Cyclic C (DC 50 =5.48 μM), along with high selectivity that had no effect on CDK1-7 and CDK9. Importantly, compound 3 could also lower the expression of Cyclin C by reducing mRNA levels, thus better reducing the content of Cyclin C and inhibiting the formation of intermediate complex composed of CDK8, Cyclin C, MED12, and MED13 so that it could better inhibit the biological function of CDK8.Mechanism studies have shown that it had a stronger inhibitory effect on the Wnt/β -catenin signaling pathway and cell cycle regulation than compound C29. This study provides new ideas for the design of CDK8 degrading agents .