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This review summarizes synthetic routes for 17 representative small-molecule CDK inhibitors that have obtained regulatory approval or are under clinical evaluation. 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Synthetic Approaches and Clinical Application of Representative Small-Molecule Inhibitors of Cyclin-Dependent Kinase for Cancer Therapy. Molecules 2024, 29, 3029. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/molecules29133029](10.3390/molecules29133029)  \nAcademic Editors: Chiara Brullo and Simona Rapposelli  \nReceived: 6 May 2024  \nRevised: 4 June 2024  \nAccepted: 11 June 2024  \nPublished: 26 June 2024  \nCopyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 First People’s Hospital of Shangqiu, Shangqiu 476100, China  \n2 Department of Anesthesiology, The First Hospital of China Medical University, Shenyang 110001, China; [clarence6660010@163.com](clarence6660010@163.com)  \n3 School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Chongqing 401331, China  \n* [Correspondence: yataowangjlu@outlook.com](Correspondence: yataowangjlu@outlook.com) (Y.-T.W.); [zhangsl@cqu.edu.cn](zhangsl@cqu.edu.cn) (S.-L.Z.)† These authors contributed equally to this work.  \nAbstract: The regulation of the cancer cell cycle heavily relies on cyclin-dependent kinases (CDKs) . Targeting CDKs has been identified as a promising approach for effective cancer therapy. In recent years, there has been significant attention paid towards developing small-molecule CDK inhibitors in the field of drug discovery. Notably, five such inhibitors have already received regulatory approval for the treatment of different cancers, including breast tumors, lung malignancies, and hematological malignancies. This review provides an overview of the synthetic routes used to produce 17 representative small-molecule CDK inhibitors that have obtained regulatory approval or are currently being evaluated through clinical trials. It also discusses their clinical applications for treating CDK-related diseases and explores the challenges and limitations associated with their use in a clinical setting, which will stimulate the further development of novel CDK inhibitors. By integrating therapeutic applications, synthetic methodologies, and mechanisms of action observed in various clinical trials involving these CDK inhibitors, this review facilitates a comprehensive understanding of the versatile roles and therapeutic potential offered by interventions targeting CDKs.  \nKeywords: CDK; synthesis; application; small molecule; drugs  \n1. Introduction  \nOne of the characteristic features of tumors is abnormal cell proliferation caused by cell division imbalance. Therefore, identifying and blocking the relevant targets of cell division is an important direction for tumor treatment. The division of eukaryotic cells follows a highly conserved process called the cell cycle. Each step of the cell cycle must occur ina sequential manner under the control of relevant signal checkpoints. CDKs control the transition from one stage of the cell cycle to the following stage. CDKs are activated when they interact with cyclins. Therefore, CDKs are potential targets for tumor treatment [1–3] . There are four phases in the cell cycle: G1 (the pre-deoxyribonucleic acid (DNA) synthesis phase), S (the DNA synthesis phase), G2 (the pre-cell division phase), and M (the cell division phase) [4] . So far, dozens of CDKs (CDK1/2/4/6/7/9, etc.) and cyclins (cyclin A/B/D/E/F/G/H, etc.) have been identified and play important roles in cell cycle regulati","cbCaioNxU9Y1NRQZ","https://ap.wps.com/l/cbCaioNxU9Y1NRQZ","pdf",3578227,22,"English","# Abstract\n# Keywords\n# Introduction\n## Tumor cell proliferation and the cell cycle\n## CDKs as therapeutic targets\n## Evolution from pan-/multi-CDK inhibitors to selective inhibitors\n## Approved CDK4/6 inhibitors and clinical relevance","[{\"question\":\"Why are cyclin-dependent kinases (CDKs) considered targets for cancer therapy?\",\"answer\":\"CDKs regulate cell-cycle transitions, and abnormal CDK expression and activity are closely linked to cancer progression. Inhibiting CDKs can disrupt tumor cell proliferation.\"},{\"question\":\"How many representative small-molecule CDK inhibitors are covered in the review?\",\"answer\":\"The review provides an overview of synthetic routes for 17 representative small-molecule CDK inhibitors that are either approved or currently evaluated in clinical trials.\"},{\"question\":\"What does the review emphasize about clinical application and limitations?\",\"answer\":\"It discusses clinical applications for CDK-related diseases and highlights challenges and limitations observed in clinical settings, supporting further development of improved CDK inhibitors.\"}]","Synthetic Approaches and Clinical Application of Representative Small-Molecule Inhibitors of Cyclin-Dependent Kinase for Cancer Therapy - Review | PDF",1789997469,55]