Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

Abstract

various linkers to palbociclib. The spectrum of CDK6-specific PROTACs was extended to von Hippel Lindau (VHL) and cellular inhibitor of apoptosis protein 1 (cIAP1) that are essential for most cancer cells and therefore less likely to be inactivated. Our VHL-based PROTAC series included compounds that were either specific for CDK6 or exhibited dual activity against CDK4 and CDK6. IAP-based PROTACs caused a combined degradation of CDK4/6 and IAPs resulting in synergistic effects on cancer cell growth. Our new degraders showed potent and long-lasting degrading activity in human and mouse cells and inhibited proliferation of several leukemia, myeloma and breast cancer cell lines. In conclusion, we show that VHL- and IAP-based PROTACs are an attractive approach for targeted degradation of CDK4/6 in cancer.