Development of PROTAC degrader probe of CDK4/6 based on DCAF16

Abstract

Treatment of breast cancer has greatly evolved during the last decades, but triple negative breast cancer (TNBC) with a higher degree of malignancy cannot be directly and effectively treated. Abnormal cell cycle is generally found in human breast cancer and other malignant tumors, and cyclin-dependent kinases (CDK) 4/6, a cell cycle-related regulatory nuclear protein, is deemed as an effective target for breast cancer treatment so far. Since DCAF16 E3 ligase is also mainly distributed in the nucleus, in this study, by combining Palbociclib and DCAF16 E3 ligase ligand KB02 with different linkers, a series of DCAF16 based CDK4/6 degraders were designed and synthesized. Among them, compound A4 showed potent inhibitory activity against CDK4/6, and decreased the level of CDK4/6 protein in MDA-MB-231 cells in a concentration- and time-dependent manner. Moreover, the toxicity of A4 in normal cells showed 7 times lower than that of Palbociclib, and A4 exhibits therapeutic potential in MDA-MB-231 xenograft models in vivo. These findings indicate that A4, as a novel CDK4/6 degrader based on DCAF16, is worthy of further investigating for the treatment of TNBC.

Keywords: CDK4/6; DCAF16; Degradation; PROTAC; TNBC.