Cyclin-dependent kinase 9 (CDK9) is a member of the transcription CDK subfamily. In this work, we preliminarily demonstrated the feasibility of CDK9 as a potent target of treatment for colorectal cancer, and a series of novel CDK9 inhibitors were rationally designed and synthesized based on the structure of AZD5438 (a pan CDKs inhibitor reported by AstraZeneca). A novel selective CDK9 inhibitor named CLZX-205, which possessed significant CDK9 inhibitory activity (IC₅₀ = 2.9 nM) with acceptable pharmacokinetic properties and antitumor efficacy in vitro and in vivo, was developed. Research on the mechanism indicated that CLZX-205 could induce apoptosis in the HCT116 cell line by inhibiting phosphorylation of RNA polymerase II at Ser2, which resulted in the inhibition of apoptosis-related genes and proteins expression, and these results were validated at the cellular and tumor tissue levels. Currently, CLZX-205 is undergoing further research as a promising candidate for CRC treatment.

中文翻译：

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用于治疗 CRC 的新型选择性 CDK9 抑制剂的鉴定：设计、合成和生物活性评估

细胞周期蛋白依赖性激酶 9 (CDK9) 是转录 CDK 亚家族的成员。在本工作中，我们初步论证了CDK9作为结直肠癌治疗有效靶点的可行性，并基于AZD5438（阿斯利康报道的全CDKs抑制剂）的结构，合理设计合成了一系列新型CDK9抑制剂。开发了一种名为 CLZX-205 的新型选择性 CDK9 抑制剂，它具有显着的 CDK9 抑制活性 (IC ₅₀ = 2.9 nM)，具有可接受的药代动力学特性和体外和体内抗肿瘤功效。机制研究表明，CLZX-205可以通过抑制RNA聚合酶II Ser2位点的磷酸化来诱导HCT116细胞系凋亡，从而抑制凋亡相关基因和蛋白的表达，并在细胞和细胞实验中得到验证。肿瘤组织水平。目前，CLZX-205作为结直肠癌治疗的有希望的候选药物正在进行进一步研究。