Cell Cycle Regulation Group, Department of Medicine, Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
Future Med Chem. 2009 Dec;1(9):1561-81. doi: 10.4155/fmc.09.110.
Progression of the cell cycle is controlled by various activating and inhibiting cellular factors. The subtle balance between these counteracting regulators in normal cells ensures proper cell cycle progression and facilitates cellular responses to a variety of stress stimuli. Key activators include cyclin-dependent kinases (CDKs) and, consequently, loss or inactivation of CDK inhibitors contributes to the escape of cancer cells from cell cycle control and hyperactivation of CDKs occurs in various neurodegenerative disorders. However, these adverse effects may be compensated by pharmacological counterparts. Inhibitors of CDKs representing various classes of compounds with diverse CDK inhibitory patterns have been developed, but inhibitors that have high selectivity and offer highly targeted activity against both cell cycle and transcriptional CDKs are of particular interest. This review focuses on pharmacological CDK inhibitors that have entered clinical trials and some compounds that have been evaluated preclinically. Recent discoveries in cell cycle regulation have provided rationales for clinical applications of CDK inhibitors in both monotherapeutic and combined therapeutic regimens.
细胞周期的进展受各种激活和抑制细胞因子的控制。在正常细胞中，这些相互拮抗的调节剂之间的微妙平衡确保了细胞周期的正常进展，并促进了细胞对各种应激刺激的反应。关键的激活剂包括细胞周期蛋白依赖性激酶（CDKs），因此，CDK 抑制剂的缺失或失活导致癌细胞逃避细胞周期控制，并且各种神经退行性疾病中 CDKs 过度激活。然而，这些不良反应可以通过药理学对应物来补偿。已经开发出了具有不同 CDK 抑制模式的各种化合物类别的 CDK 抑制剂，但具有高选择性并针对细胞周期和转录 CDK 具有高度靶向活性的抑制剂特别受到关注。本综述重点介绍了已进入临床试验的药理学 CDK 抑制剂和一些已进行临床前评估的化合物。细胞周期调控的最新发现为 CDK 抑制剂在单一治疗和联合治疗方案中的临床应用提供了依据。
