Development of PROTAC Degrader Probe of CDK46 Based on DCAF16

With the improvement of medical treatment, breast cancer has become one of the solid tumors with the best curative effect, but triple negative breast cancer (TNBC) with a higher degree of malignancy cannot be directly and effectively treated. Abnormal cell cycle is commonly found in human breast cancer and other malignant tumors, and CDK4/6, 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 nuclear, 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 strong 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 with its toxicity 7 times lower than that of Palbociclib, which is worthy of further investigating against TNBC.