Therapeutic targeting of transcriptional cyclin-dependent kinases.
Therapeutic targeting of transcriptional cyclin-dependent kinases.
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DOI：
10.1080/21541264.2018.1539615
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发表时间：
2019-04
期刊：
影响因子：
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通讯作者：
Espinosa JM
中科院分区：
文献类型：
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作者：
Galbraith MD;Bender H;Espinosa JM
许多癌症类型显示由致癌增强子和转录因子的失调驱动的转录成瘾的事实已经导致对一组蛋白激酶（称为转录细胞周期蛋白依赖性激酶（tCDK））作为潜在治疗靶标的兴趣增加。尽管早期对靶向对健康细胞类型至关重要的过程持保留态度，但现在有证据表明靶向tCDKs可以提供足够的治疗窗口，以在临床上有效。在这里，我们讨论了这一领域的最新进展，重点是高选择性抑制剂和这些抑制剂可用于治疗目的之前要解决的挑战。缩略语：CAK：CDK激活激酶; CDK：细胞周期蛋白依赖性激酶; CMGC集团：CDK-、MAPK-、GSK 3-和CLK-样;CTD：RNA聚合酶II RPB 1亚基的C-末端重复结构域; DR B：5，6-二氯-1-β-D-呋喃核糖基苯并咪唑;mCRPC：转移性去势抵抗性前列腺癌;NSCLC：非小细胞肺癌; P-TEF B：阳性延伸因子B;RNAPII：RNA聚合酶II;S2：CTD重复序列的丝氨酸-2;S5：CTD重复序列的丝氨酸-5;S7：CTD重复序列的丝氨酸-7;SEC：超延伸复合物;tCDK：转录细胞周期蛋白依赖性激酶;TNBC：三阴性乳腺癌
The fact that many cancer types display transcriptional addiction driven by dysregulation of oncogenic enhancers and transcription factors has led to increased interest in a group of protein kinases, known as transcriptional cyclin dependent kinases (tCDKs), as potential therapeutic targets. Despite early reservations about targeting a process that is essential to healthy cell types, there is now evidence that targeting tCDKs could provide enough therapeutic window to be effective in the clinic. Here, we discuss recent developments in this field, with an emphasis on highly-selective inhibitors and the challenges to be addressed before these inhibitors could be used for therapeutic purposes. Abbreviations: CAK: CDK-activating kinase;CDK: cyclin-dependent kinase;CMGC group: CDK-, MAPK-, GSK3-, and CLK-like;CTD: C-terminal repeat domain of the RPB1 subunit of RNA polymerase II;DRB: 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole;mCRPC: metastatic castration-resistant prostate cancer;NSCLC: non-small cell lung cancer;P-TEFb: positive elongation factor b;RNAPII: RNA polymerase II;S2: serine-2 of CTD repeats;S5: serine-5 of CTD repeats;S7: serine-7 of CTD repeats;SEC: super elongation complex;tCDK: transcriptional cyclin-dependent kinase;TNBC: triple-negative breast cancer