Department of Neurology, Neuro-system and Multimorbidity Laboratory and State Key Laboratory of Biotherapy and Cancer Center and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China.
West China College of Medicine, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China.
J Med Chem. 2024 Apr 11;67(7):5185-5215. doi: 10.1021/acs.jmedchem.4c00312. Epub 2024 Apr 2.
CDK9 is a cyclin-dependent kinase that plays pivotal roles in multiple cellular functions including gene transcription, cell cycle regulation, DNA damage repair, and cellular differentiation. Targeting CDK9 is considered an attractive strategy for antitumor therapy, especially for leukemia and lymphoma. Several potent small molecule inhibitors, exemplified by (), have progressed to clinical trials. However, many of them face challenges such as low clinical efficacy and multiple adverse reactions and may necessitate the exploration of novel strategies to lead to success in the clinic. In this perspective, we present a comprehensive overview of the structural characteristics, biological functions, and preclinical status of CDK9 inhibitors. Our focus extends to various types of inhibitors, including pan-inhibitors, selective inhibitors, dual-target inhibitors, degraders, PPI inhibitors, and natural products. The discussion encompasses chemical structures, structure-activity relationships (SARs), biological activities, selectivity, and therapeutic potential, providing detailed insight into the diverse landscape of CDK9 inhibitors.
CDK9 是一种细胞周期蛋白依赖性激酶，在多种细胞功能中发挥关键作用，包括基因转录、细胞周期调控、DNA 损伤修复和细胞分化。靶向 CDK9 被认为是抗肿瘤治疗的一种有吸引力的策略，特别是对于白血病和淋巴瘤。几种有效的小分子抑制剂，例如 ()，已经进入临床试验。然而，它们中的许多都面临着临床疗效低和多种不良反应等挑战，可能需要探索新的策略，以在临床上取得成功。在这篇观点文章中，我们全面概述了 CDK9 抑制剂的结构特征、生物学功能和临床前状态。我们的重点扩展到各种类型的抑制剂，包括泛抑制剂、选择性抑制剂、双靶抑制剂、降解剂、PPI 抑制剂和天然产物。讨论包括化学结构、构效关系 (SAR)、生物学活性、选择性和治疗潜力，深入了解 CDK9 抑制剂的多样化景观。
