We successfully synthesized a Von Hippel-Lindau (VHL) based CDK4/6-targeting PROTAC (Fig. 1 and Supplementary Fig. 1), which has the capacity of CDK4/6 protein degradation and phosphorylated retinoblastoma (Rb (phospho S807)) downregulation in mice CRC CT26 cells (Fig. 2a) and human breast cancer MDA-MB-231 cells (Supplementary Fig. 2) in a concentration- and time-dependent manner. Here, RB1 is linked to breast cancer.