Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders
Christian Steinebach, Yuen Lam Dora Ng, Izidor Sosič, Chih-Shia Lee, Sirui Chen, Stefanie Lindner, Lan Phuong Vu, Aleša Bricelj, Reza Haschemi, Marius Monschke, Elisabeth Steinwarz, Karl Wagner, Gerd Bendas, Ji Luo, Michael Gütschow, Jan Krönke
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.