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.

由细胞周期失调和细胞周期蛋白依赖性激酶（CDKs）激活导致的持续细胞增殖是癌症的标志。抑制CDKs是开发抗癌药物的高度有前途和有吸引力的策略。特别是，第三代CDK抑制剂可以通过抑制G1到S相的转变来选择性抑制CDK4 / 6并调节细胞周期，从而在抗癌功效和一般毒性之间展现出完美的平衡。迄今为止，三种选择性CDK4 / 6抑制剂已获得美国食品和药物管理局（FDA）的批准，并且有15种CDK4 / 6抑制剂正在治疗癌症的临床试验中。从这个角度，我们讨论了CDK4 / 6在调节细胞周期和癌细胞中的关键作用，