Anshabo Abel Tesfaye, Milne Robert, Wang Shudong, Albrecht Hugo
Drug Discovery and Development, Centre for Cancer Diagnostics and Therapeutics, Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia.
Front Oncol. 2021 May 10;11:678559. doi: 10.3389/fonc.2021.678559. eCollection 2021.
Cyclin-dependent kinases (CDKs) are proteins pivotal to a wide range of cellular functions, most importantly cell division and transcription, and their dysregulations have been implicated as prominent drivers of tumorigenesis. Besides the well-established role of cell cycle CDKs in cancer, the involvement of transcriptional CDKs has been confirmed more recently. Most cancers overtly employ CDKs that serve as key regulators of transcription (e.g., CDK9) for a continuous production of short-lived gene products that maintain their survival. As such, dysregulation of the CDK9 pathway has been observed in various hematological and solid malignancies, making it a valuable anticancer target. This therapeutic potential has been utilized for the discovery of CDK9 inhibitors, some of which have entered human clinical trials. This review provides a comprehensive discussion on the structure and biology of CDK9, its role in solid and hematological cancers, and an updated review of the available inhibitors currently being investigated in preclinical and clinical settings.
细胞周期蛋白依赖性激酶（CDKs）是对广泛的细胞功能至关重要的蛋白质，其中最重要的是细胞分裂和转录，其失调被认为是肿瘤发生的主要驱动因素。除了细胞周期CDKs在癌症中已确立的作用外，转录CDKs的参与最近也得到了证实。大多数癌症明显利用作为转录关键调节因子的CDKs（例如CDK9）来持续产生维持其生存的短寿命基因产物。因此，在各种血液系统和实体恶性肿瘤中都观察到CDK9途径的失调，使其成为一个有价值的抗癌靶点。这种治疗潜力已被用于发现CDK9抑制剂，其中一些已进入人体临床试验。本综述全面讨论了CDK9的结构和生物学、其在实体和血液系统癌症中的作用，以及对目前正在临床前和临床环境中研究的可用抑制剂的最新综述。
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