Galbraith Matthew D, Bender Heather, Espinosa Joaquín M
a Linda Crnic Institute for Down Syndrome, School of Medicine , University of Colorado Anschutz Medical Campus , Aurora , CO , USA.
b Department of Pharmacology, School of Medicine , University of Colorado Anschutz Medical Campus , Aurora , CO , USA.
Transcription. 2019 Apr;10(2):118-136. doi: 10.1080/21541264.2018.1539615. Epub 2018 Nov 9.
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.
许多癌症类型表现出由致癌增强子和转录因子失调驱动的转录成瘾，这一事实引发了人们对一组被称为转录细胞周期蛋白依赖性激酶（tCDK）的蛋白激酶作为潜在治疗靶点的兴趣增加。尽管早期对靶向一个对健康细胞类型至关重要的过程存在保留意见，但现在有证据表明，靶向tCDK可以提供足够的治疗窗口，从而在临床上有效。在此，我们讨论该领域的最新进展，重点是高选择性抑制剂以及在这些抑制剂可用于治疗目的之前需要解决的挑战。缩写：CAK：CDK激活激酶；CDK：细胞周期蛋白依赖性激酶；CMGC组：CDK、MAPK、GSK3和CLK样；CTD：RNA聚合酶II的RPB1亚基的C末端重复结构域；DRB：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-TEFb：正性延伸因子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：超级延伸复合物；tCDK：转录细胞周期蛋白依赖性激酶；TNBC：三阴性乳腺癌。
