cdk 抑制剂在抗肿瘤领域的研发进展 - 药学进展.pdf

PROGRESS IN PHARMACEUTICAL SCIENCES 2015,39 10 :734-745 734 ( ) CDK 抑制剂在抗肿瘤领域的研发进展 谢韶，丁健，陈奕* （中国科学院上海药物研究所新药研究国家重点实验室肿瘤药理组，上海 201203） [ 摘要 ] 细胞周期蛋白依赖性激酶（cyclin dependent kinase，CDK）为细胞周期调节的关键激酶，参与细胞增殖、转录、存活等生理过程。 CDK 在多种肿瘤中异常活化，是抗肿瘤药物研发的重要靶点之一。目前已有 1 个 CDK 抑制剂（palbociclib, CDK4/CDK6 抑制剂）被美国 食品药品监督管理局批准于 2015 年上市，数十个 CDK 抑制剂处于针对实体瘤和血液系统肿瘤的临床或临床前研究阶段。综述目前抗肿瘤 领域 CDK 抑制剂的研发现状、遇到的问题和可能的解决方案，并讨论其临床应用的可能。 [ 关键词 ] CDK；抑制剂；ATP 竞争；非 ATP 竞争；联合用药 [ 中图分类号 ] R966;R962 [ 文献标志码 ] A [ 文章编号 ] 1001-5094（2015）10-0734-12 Progress in Development of Cyclin-dependent Kinase Inhibitors as Cancer Therapy XIE Shao, DING Jian, CHEN Yi (Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China) [Abstract] Cyclin-dependent kinases(CDKs) play critical roles in controlling cell cycle and regulating cell proliferation, transcription and survival. CDKs are often abnormally activated in numerous tumors and thus become attractive anticancer targets. Palbociclib, a CDK4/CDK6 inhibitor, was approved by the US Food and Drugs Administration in 2015, Dozens of compounds targeting CDKs are currently in clinical development for various solid tumors and hematopoietic malignances.In this article, the recent studies on CDK inhibitors, related challenges and solutions were reviewed, and the probable clinical application of CDK inhibitors was also discussed. [Key words] CDK; inhibitor; ATP competitive; non-ATP competitive; combined therapy 过度活化、持续的细胞增殖是肿瘤的一个基本特 与转录因子E2F 结合并抑制其活性，抑制增殖，使细 G0 征，因此诱导细胞周期阻滞可有效