Selective inhibition of CDK4/6: A safe and effective strategy for developing anticancer drugs

摘要

The sustained cell proliferation resulting from dysregulation of the cell cycle and activation of cyclin-dependent kinases(CDKs)is a hallmark of cancer.The inhibition of CDKs is a highly promising and attractive strategy for the development of anticancer drugs.In particular,third-generation CDK inhibitors can selectively inhibit CDK4/6 and regulate the cell cycle by suppressing the G1 to S phase transition,exhibiting a perfect balance between anticancer efficacy and general toxicity.To date,three selective CDK4/6 inhibitors have received approval from the U.S.Food and Drug Administration(FDA),and 15 CDK4/6 inhibitors are in clinical trials for the treatment of cancers.In this perspective,we discuss the crucial roles of CDK4/6 in regulating the cell cycle and cancer cells,analyze the rationale for selectively inhibiting CDK4/6 for cancer treatment,review the latest advances in highly selective CDK4/6 inhibitors with different chemical scaffolds,explain the mechanisms associated with CDK4/6inhibitor resistance and describe solutions to overcome this issue,and briefly introduce proteolysis targeting chimera(PROTAC),a new and revolutionary technique used to degrade CDK4/6.