Cyclin-dependent Kinase 11: Cellular Functions and Potential Therapeutic Applications.

IF 3.6 4区医学 Q2 CHEMISTRY, MEDICINAL

ChemMedChem Pub Date : 2025-07-08 DOI:10.1002/cmdc.202500305

Janhabee Shrestha, Jason Blanchard, Solomon Tadesse

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引用次数: 0

Abstract

Cyclin-dependent kinase 11 (CDK11) is a multifunctional serine/threonine protein kinase that plays a pivotal role in transcription and pre-mRNA splicing. It phosphorylates serine 2 of RNA polymerase II C-terminal domain, thereby promoting transcriptional elongation and 3'-end processing of replication-dependent histone genes, as well as contributing to proper chromosome segregation during mitosis. CDK11 is essential for global pre-mRNA splicing by phosphorylating Splicing Factor 3B Subunit 1, a core U2 small nuclear ribonucleoprotein component, thereby activating the spliceosome. Since splicing is closely linked to optimal transcription and cell proliferation, inhibition of CDK11 is hypothesized to indirectly disrupt general transcription and cell cycle progression. CDK11 drives cancer cell proliferation, promotes HIV-1 mRNA 3'-end processing to enhance viral replication, and contributes to tau phosphorylation in Alzheimer's disease. Given its integral role in key cellular processes and its dysregulation in various diseases, CDK11 has emerged as a compelling therapeutic target. This review provides a comprehensive overview of the biological functions and regulatory mechanisms of CDK11, discusses its role in cancer, viral and neurodegenerative diseases, and highlights advances in the discovery and development of CDK11 inhibitors, including OTS964, which has expanded our understanding of the biological functions of CDK11 and its prospects as a cancer-specific vulnerability.

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细胞周期蛋白依赖性激酶11：细胞功能和潜在的治疗应用。

细胞周期蛋白依赖性激酶11 （CDK11）是一种多功能丝氨酸/苏氨酸蛋白激酶，在转录和mrna前剪接中起关键作用。它磷酸化RNA聚合酶II c端结构域的丝氨酸2，从而促进复制依赖性组蛋白基因的转录延伸和3'端加工，并有助于有丝分裂过程中染色体的适当分离。CDK11通过磷酸化剪接因子3B亚基1（一个核心的U2小核核糖核蛋白成分），从而激活剪接体，对全局pre-mRNA剪接至关重要。由于剪接与最佳转录和细胞增殖密切相关，因此假设抑制CDK11可间接破坏一般转录和细胞周期进程。CDK11驱动癌细胞增殖，促进HIV-1 mRNA 3'端加工以增强病毒复制，并在阿尔茨海默病中参与tau磷酸化。鉴于其在关键细胞过程中的整体作用及其在各种疾病中的失调，CDK11已成为一个引人注目的治疗靶点。本文综述了CDK11的生物学功能和调控机制，讨论了其在癌症、病毒和神经退行性疾病中的作用，并重点介绍了包括OTS964在内的CDK11抑制剂的发现和开发进展，这些进展扩大了我们对CDK11生物学功能及其作为癌症特异性易感性的前景的理解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ChemMedChem 医学-药学

CiteScore

6.70

自引率

2.90%

发文量

280

审稿时长

1 months

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