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

• Main Authors: Kai Yuan, Xiao Wang, Haojie Dong, Wenjian Min, Haiping Hao, Peng Yang
• Format: Article
• Language: English
• Published: Elsevier 2021-01-01
• Series: Acta Pharmaceutica Sinica B
• Subjects: CDK4/6; Cell cycle; Cancer; Selectivity; Drug resistance; PROTAC
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211383520305839

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 CDK4/6 inhibitor 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.