College of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing, 312000, China.
Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China.
Eur J Med Chem. 2019 Feb 15;164:77-91. doi: 10.1016/j.ejmech.2018.11.076. Epub 2018 Dec 21.
Cyclin-dependent kinases 8 (CDK8) regulates transcriptional process via associating with the mediator complex or phosphorylating transcription factors (TF). Overexpression of CDK8 has been observed in various cancers. It mediates aberrant activation of Wnt/β-catenin signaling pathway, which is initially recognized and best studied in colorectal cancer (CRC). CDK8 acts as an oncogene and represents a potential target for developing novel CDK8 inhibitors in cancer therapeutics. However, other study has revealed its contrary role. The function of CDK8 is context dependent. Even so, a variety of potent and selective CDK8 inhibitors have been discovered after crystal structures were resolved in two states (active or inactive). In this review, we summarize co-crystal structures, biological mechanisms, dysregulation in cancers and recent progress in the field of CDK8 inhibitors, trying to offer an outlook of CDK8 inhibitors in cancer therapy in future.
周期蛋白依赖性激酶 8（CDK8）通过与中介复合物结合或磷酸化转录因子（TF）来调节转录过程。在各种癌症中都观察到 CDK8 的过表达。它介导 Wnt/β-catenin 信号通路的异常激活，该通路最初在结直肠癌（CRC）中被识别并得到了最好的研究。CDK8 作为一种癌基因，代表了在癌症治疗中开发新型 CDK8 抑制剂的潜在靶点。然而，其他研究揭示了它相反的作用。CDK8 的功能取决于上下文。即便如此，在两种状态（活性或非活性）下解析晶体结构后，已经发现了多种有效且选择性的 CDK8 抑制剂。在这篇综述中，我们总结了共晶体结构、生物学机制、在癌症中的失调以及 CDK8 抑制剂领域的最新进展，试图为 CDK8 抑制剂在未来癌症治疗中的应用提供展望。
