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Recent Discovery and Development of Inhibitors that Target CDK9 and Their Therapeutic Indications
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-04-02 , DOI: 10.1021/acs.jmedchem.4c00312 Yuming Zhang 1, 2 , Lianhai Shan 3 , Wentao Tang 1 , Yating Ge 1 , ChengXian Li 1 , Jifa Zhang 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-04-02 , DOI: 10.1021/acs.jmedchem.4c00312 Yuming Zhang 1, 2 , Lianhai Shan 3 , Wentao Tang 1 , Yating Ge 1 , ChengXian Li 1 , Jifa Zhang 1
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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 TG02 (4), 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.
中文翻译：
针对 CDK9 的抑制剂的最新发现和开发及其治疗适应症
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着关键作用，包括基因转录、细胞周期调节、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，尤其是针对白血病和淋巴瘤。以TG02 ( 4 ) 为代表的几种有效的小分子抑制剂已进入临床试验。然而，其中许多面临着临床疗效低下和多种不良反应等挑战，可能需要探索新的策略才能在临床上取得成功。从这个角度来看，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。我们的重点延伸到各种类型的抑制剂，包括泛抑制剂、选择性抑制剂、双靶点抑制剂、降解剂、PPI抑制剂和天然产物。讨论涵盖化学结构、构效关系 (SAR)、生物活性、选择性和治疗潜力，为 CDK9 抑制剂的多样化景观提供了详细的见解。
更新日期：2024-04-02
中文翻译：
针对 CDK9 的抑制剂的最新发现和开发及其治疗适应症
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着关键作用，包括基因转录、细胞周期调节、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，尤其是针对白血病和淋巴瘤。以TG02 ( 4 ) 为代表的几种有效的小分子抑制剂已进入临床试验。然而，其中许多面临着临床疗效低下和多种不良反应等挑战，可能需要探索新的策略才能在临床上取得成功。从这个角度来看，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。我们的重点延伸到各种类型的抑制剂，包括泛抑制剂、选择性抑制剂、双靶点抑制剂、降解剂、PPI抑制剂和天然产物。讨论涵盖化学结构、构效关系 (SAR)、生物活性、选择性和治疗潜力，为 CDK9 抑制剂的多样化景观提供了详细的见解。
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