细胞周期机器的去调节是癌症的关键特征之一，与周期蛋白依赖性激酶（CDK）的失调有关，最终促进了异常增殖，从而推动了肿瘤发生和疾病发展。因此，最近几十年间开发了多种CDK抑制剂（CDKI）以抑制癌细胞增殖，包括第一代、第二代和第三代CDKI。由于其特异性有限和毒性较高，第一代和第二代CDKI并未受到临床治疗癌症患者的重视。然而，最近发展的联合治疗策略使我们可以减少这些CDKI的毒性和副作用，为它们在临床应用中的潜在应用铺平了道路。第三代CDKI在临床前和临床试验中取得了最有希望的结果，将它们推进了针对多种恶性肿瘤的临床试验的高级阶段，尤其是乳腺癌，并改变了传统的治疗策略。在本综述中，我们讨论了第一代、第二代和第三代CDKI中最受关注的候选药物、它们的基本作用机制、过去失败的原因以及它们目前在不同恶性肿瘤治疗中的临床开发情况。此外，我们简要介绍了最新的临床试验结果和FDA批准的第三代选择性CDK4/6抑制剂在对抗最普遍的癌症方面的进展。总体而言，本综述将从过去到现在全面了解CDKI，让研究人员重新思考和开发创新的癌症治疗方案。版权所有©2022 Elsevier Ltd.

Deregulation of the cell cycle machinery, which has been linked to dysregulation of cyclin-dependent kinases (CDKs), is a defining characteristic of cancer, eventually promoting abnormal proliferation that feeds tumorigenesis and disease development. In this regard, several CDK inhibitors (CDKIs) have been developed during the last few decades (1st, 2nd, and 3rd generation CDKIs) to inhibit cancer cell proliferation. 1st and 2nd generation CDKIs have not received much clinical attention for the treatment of cancer patients because of their limited specificity and high toxicity. However, the recent development of combination strategies allowed us to reduce the toxicity and side effects of these CDKIs, paving the way for their potential application in clinical settings. The 3rd generation CDKIs have yielded the most promising results at the preclinical and clinical levels, propelling them into the advanced stages of clinical trials against multiple malignancies, especially breast cancer, and revolutionizing traditional treatment strategies. In this review, we discuss the most-investigated candidates from the 1st, 2nd, and 3rd generations of CDKIs, their basic mechanisms of action, the reasons for their failure in the past, and their current clinical development for the treatment of different malignancies. Additionally, we briefly highlighted the most recent clinical trial results and advances in the development of 3rd generation FDA-approved selective CDK4/6 inhibitors that combat the most prevalent cancer. Overall, this review will provide a thorough knowledge of CDKIs from the past to the present, allowing researchers to rethink and develop innovative cancer therapeutic regimens.Copyright © 2022 Elsevier Ltd. All rights reserved.