Cryo-EM catalyzes the exploration of drug selectivity: The CDK7 inhibitor example.
Cryo-EM catalyzes the exploration of drug selectivity: The CDK7 inhibitor example.
复制标题
冷冻电镜催化药物选择性的探索：CDK7 抑制剂示例。
DOI：
10.1016/j.bpj.2021.02.010
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发表时间：
2021
影响因子：
3.4
通讯作者：
Samsó,Montserrat
中科院分区：
文献类型：
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作者：
Samsó,Montserrat
人细胞周期蛋白依赖性激酶7(CDK7)与细胞周期蛋白H和MAT1形成复合体，形成CDK激活激酶(CAK)复合体，对参与细胞周期调控的其他CDK起下游作用。CAK通过激活CDK1、-2、-4和-6各自的调节T-环(1)来激活它们。当被激活时，这些CDK中的每一个都促进了沿着真核细胞周期进程通过特定检查点的过渡。CAK还形成转录因子IIH(TFIIH)复合体的一部分，并磷酸化RNA POL II最大亚单位的C-末端结构域，这是启动和启动转录延伸所需的步骤(2，3)。作为细胞周期和转录的激活剂，CDK7成为开发旨在减缓癌细胞生长的抑制剂的有吸引力的候选者。到目前为止，CDKs的ATP结合口袋是开发CDK7合成抑制剂的最大靶点。然而，可能由于不同CDK的ATP结合口袋之间的相似性，使得第一代作用于多个CDK的选择性化合物一直难以制备。少数第二代化合物增加了
Human cyclin-dependent kinase 7 (CDK7), in complex with cyclin H and MAT1, form the CDK-activating kinase (CAK) complex that has a downstream effect on other CDKs involved in cell cycle control. CAK activates CDK1,-2,-4, and-6 via phosphorylation of their respective regulatory T-loops (1). When activated, each of these CDKs facilitates transition through a specific checkpoint along the eukaryotic cell cycle progression. CAK also forms part of the transcription factor IIH (TFIIH) complex and phosphorylates the C-terminal domain of the largest subunit of RNA Pol II, a step required to initiate and set off transcription elongation (2, 3). Being an activator of both cell cycle and transcription makes CDK7 an attractive candidate for development of inhibitors aimed at slowing down the growth of cancer cells.The ATP binding pocket of CDKs is, so far, the most targeted for the development of synthetic inhibitors for CDK7. However, probably owing to the similarities among the ATP binding pocket of the different CDKs, it has been difficult to make selective compounds such that the first generation acted on multiple CDKs. A handful of secondgeneration compounds had increased