Laboratory of Growth Regulators, Palacký University & Institute of Experimental Botany AS CR, 78371 Olomouc, Czech Republic.
Curr Drug Targets. 2010 Mar;11(3):291-302. doi: 10.2174/138945010790711950.
Poor therapeutic outcomes and serious side effects, together with acquired resistance to multiple drugs, are common problems of current cancer therapies. Therefore, there is an urgent need for new cancer-targeted drugs, which has led (inter alia) to the development of molecules that can specifically inhibit cyclin-dependent kinases (CDKs). In addition to their cell cycle regulatory functions, CDKs, especially CDK7 and CDK9, play important roles in the regulation of RNA polymerase II-mediated transcription. Here, we report on progress in the preclinical development of CDK inhibitors and their anticancer activities. Special attention is paid to the action mechanisms of the pan-specific CDK inhibitors flavopiridol and roscovitine, which have already entered phase II clinical trials as treatments for various tumours. The links between their ability to inhibit transcription and sensitisation of some types of cancer to apoptosis, mechanisms leading to p53 activation, and their synergistic cooperation with common DNA damaging drugs are also discussed. It has been demonstrated that drug-resistant cancer cells can arise during therapeutic application of small molecule protein kinase inhibitors. Clinical resistance to CDK inhibitors has not yet been described, but by comparing CDKs to other kinases, and CDK inhibitors to other clinically used protein kinase inhibitors, we also discuss possible mechanisms that could lead to resistance to CDK inhibitors.
目前癌症治疗存在疗效差和副作用大，以及对多种药物产生获得性耐药的问题。因此，迫切需要新的癌症靶向药物，这导致了（除其他外）能够特异性抑制细胞周期蛋白依赖性激酶（CDK）的分子的发展。除了细胞周期调节功能外，CDK，特别是 CDK7 和 CDK9，在 RNA 聚合酶 II 介导体转录的调节中发挥着重要作用。本文报告了 CDK 抑制剂的临床前开发及其抗癌活性的进展。特别关注泛特异性 CDK 抑制剂 flavopiridol 和 roscovitine 的作用机制，它们已作为治疗各种肿瘤的药物进入 II 期临床试验。还讨论了它们抑制转录的能力与某些类型的癌症对细胞凋亡的敏感性之间的联系、导致 p53 激活的机制，以及它们与常见的 DNA 损伤药物的协同合作。已经证明，在小分子蛋白激酶抑制剂的治疗应用中会出现耐药性癌症细胞。尚未描述对 CDK 抑制剂的临床耐药性，但通过将 CDKs 与其他激酶进行比较，以及将 CDK 抑制剂与其他临床上使用的蛋白激酶抑制剂进行比较，我们还讨论了可能导致对 CDK 抑制剂产生耐药性的机制。
