Nature Chemical Biology ( IF 14.8 ) Pub Date : 2020-06-22 , DOI: 10.1038/s41589-020-0563-4 Pabitra K Parua 1 , Robert P Fisher 1
Largely non-overlapping sets of cyclin-dependent kinases (CDKs) regulate cell division and RNA polymerase II (Pol II)-dependent transcription. Here we review the molecular mechanisms by which specific CDKs are thought to act at discrete steps in the transcription cycle and describe the recent emergence of transcriptional CDKs as promising drug targets in cancer. We emphasize recent advances in understanding the transcriptional CDK network that were facilitated by development and deployment of small-molecule inhibitors with increased selectivity for individual CDKs. Unexpectedly, several of these compounds have also shown selectivity in killing cancer cells, despite the seemingly universal involvement of their target CDKs during transcription in all cells. Finally, we describe remaining and emerging challenges in defining functions of individual CDKs in transcription and co-transcriptional processes and in leveraging CDK inhibition for therapeutic purposes.
中文翻译:
剖析Pol II转录周期并用CDK抑制剂破坏癌症。
大部分非重叠的细胞周期蛋白依赖性激酶(CDK)调节细胞分裂和RNA聚合酶II(Pol II)依赖性转录。在这里,我们审查了特定CDK被认为在转录周期中离散步骤起作用的分子机制,并描述了转录CDK作为癌症中有希望的药物靶标的最新出现。我们强调了解转录CDK网络的最新进展,这是由于小分子抑制剂的开发和部署以及对单个CDK选择性的提高而促进的。出乎意料的是,尽管这些化合物的目标CDK在所有细胞的转录过程中似乎普遍参与,但其中的几种化合物也显示出杀死癌细胞的选择性。最后,