大量证据表明，CDK2-细胞周期蛋白 A/E 复合物的过度表达会破坏正常的细胞周期调节，导致癌细胞增殖失控。因此，CDK2已成为癌症治疗的一个有前途的治疗靶点。近年来，对CDK2催化位点和变构袋结构的深入了解为开发更有效的临床CDK2抑制剂候选物提供了显着的机会。本文回顾了已进入临床试验的最新CDK2抑制剂，并讨论了其设计和发现近年来最有前途的新型临床前CDK2抑制剂。此外，它还总结了变构 CDK2 抑制剂和 CDK2 靶向 PROTAC 的发展。该审查涵盖抑制剂和 PROTAC 设计、结构-活性关系以及体外和体内生物学评估的策略。尽管付出了巨大的努力，但由于选择性差和在临床环境中观察到的毒性，尚未有 CDK2 抑制剂获得 FDA 批准上市。 。未来的研究必须优先考虑 CDK2 抑制剂和 PROTAC 的选择性、效力和药代动力学的优化。此外，探索将 CDK2 抑制剂与其他靶向药物相结合的联合疗法，或多靶点抑制剂的设计，为推进癌症治疗策略带来了重大希望。

Abundant evidence suggests that the overexpression of CDK2-cyclin A/E complex disrupts normal cell cycle regulation, leading to uncontrolled proliferation of cancer cells. Thus, CDK2 has become a promising therapeutic target for cancer treatment. In recent years, insights into the structures of the CDK2 catalytic site and allosteric pockets have provided notable opportunities for developing more effective clinical candidates of CDK2 inhibitors.This article reviews the latest CDK2 inhibitors that have entered clinical trials and discusses the design and discovery of the most promising new preclinical CDK2 inhibitors in recent years. Additionally, it summarizes the development of allosteric CDK2 inhibitors and CDK2-targeting PROTACs. The review encompasses strategies for inhibitor and PROTAC design, structure-activity relationships, as well as in vitro and in vivo biological assessments.Despite considerable effort, no CDK2 inhibitor has yet received FDA approval for marketing due to poor selectivity and observed toxicity in clinical settings. Future research must prioritize the optimization of the selectivity, potency, and pharmacokinetics of CDK2 inhibitors and PROTACs. Moreover, exploring combination therapies incorporating CDK2 inhibitors with other targeted agents, or the design of multi-target inhibitors, presents significant promise for advancing cancer treatment strategies.