Cyclin-dependent kinase inhibitors
Cyclin-dependent kinase inhibitors
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DOI：
10.1016/s1471-4892(03)00079-1
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发表时间：
2003-08-01
影响因子：
4
通讯作者：
Grant, S
中科院分区：
文献类型：
--
作者：
Dai, Y;Grant, S
细胞周期失调是肿瘤细胞的主要特征之一。由于这个原因，靶向细胞周期蛋白依赖性激酶（CDK）的小分子抑制剂（其中夫拉匹醇是原型）已经成为癌症治疗中广泛关注的焦点。除了抑制细胞周期进程外，这些药物还表现出多种其他活性，包括诱导细胞死亡。最近，几种新的作用机制已被归因于CDK抑制剂flavopiridol，包括干扰转录，最有可能通过破坏P-TEFb（即CDK 9/细胞周期蛋白T复合物），和诱导细胞凋亡，可能是各种抗凋亡蛋白下调的结果。还观察到，在多种临床前模型中，将CDK抑制剂与常规细胞毒性药物或新型信号转导调节剂组合显著促进肿瘤细胞死亡。目前正在努力发现选择性靶向特定CDK的抑制剂，并将其开发为新一代抗肿瘤药物。由于所有这些原因，在可预见的未来，对CDK抑制剂作为抗肿瘤剂的兴趣可能会继续。
Cell-cycle dysregulation is one of the cardinal characteristics of neoplastic cells. For this reason, small molecule inhibitors targeting cyclin-dependent kinases (CDKs), of which flavopiridol is a prototype, have been the focus of extensive interest in cancer therapy. In addition to inhibiting cell-cycle progression, these agents exhibit a variety of other activities, including the induction of cell death. Recently, several novel mechanisms of action have been ascribed to the CDK inhibitor flavopiridol, including interference with transcription, most likely through disruption of P-TEFb (i.e. the CDK9/cyclin T complex), and induction of apoptosis, possibly a consequence of downregulation of various anti-apoptotic proteins. It has also been observed that combining CDK inhibitors with either conventional cytotoxic drugs or novel signal transduction modulators dramatically promotes neoplastic cell death in a variety of preclinical models. Efforts are underway to uncover inhibitors that selectively target specific CDKs and to develop these as a new generation of antitumour drugs. For all of these reasons, it is likely that interest in CDK inhibitors as antineoplastic agents will continue for the foreseeable future.