Chen Sumeng, Huang Jindi, Zhang Shipeng, Zheng Xinni, Chen Hongming, Chen Tie-Gen, Wang Ling
Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering, Joint International Research Laboratory of Synthetic Biology and Medicine, Ministry of Education, Guangdong Provincial Engineering and Technology Research Center of Biopharmaceuticals, School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China.
Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China.
Bioorg Chem. 2025 Jun 15;160:108436. doi: 10.1016/j.bioorg.2025.108436. Epub 2025 Apr 5.
CDK9 plays a vital role in cellular transcriptional regulation. Hyper-activation of CDK9 leads to the occurrence of various cancers including acute myeloid leukemia, thereby rendering CDK9 an attractive target for cancer treatment. Based on hit compound A4 with 2,5-disubstituted thiazole core identified through the SyntaLinker-Hybrid scheme that shows weak inhibitory activity against both CDK9 and MOLM-13 cells, we designed and synthesized 32 derivatives through structural modification. In vitro anti-proliferative test screened and confirmed that 14 compounds showed highly inhibitory activity against MOLM-13 cells with IC values in the micromolar range. Among them, compound 24 displayed the best antiproliferative activity against MOLM-13 cells with an IC value of 0.034 μM, which was comparable to the positive drug (BAY1251152, IC = 0.031 μM). In vitro kinase inhibition assay results demonstrated that compound 24 had considerable inhibitory activity against CDK9 with an IC value of 5.5 nM and a weak inhibitory activity on other CDKs. Further cellular mechanism assays revealed that 24 affected CDK9 signaling pathways, induced cellular apoptosis and arrested cell cycle in the G2/M phase. Finally, further studies of compound 24 about molecular docking, molecular dynamics simulations and ADMET prediction were investigated. Collectively, compound 24 deserves further structural optimization and development for the treatment of acute myeloid leukemia.
细胞周期蛋白依赖性激酶9（CDK9）在细胞转录调控中起着至关重要的作用。CDK9的过度激活会导致包括急性髓系白血病在内的各种癌症的发生，因此使CDK9成为一个有吸引力的癌症治疗靶点。基于通过SyntaLinker-Hybrid方案鉴定出的具有2,5-二取代噻唑核心的命中化合物A4，其对CDK9和MOLM-13细胞均显示出微弱的抑制活性，我们通过结构修饰设计并合成了32种衍生物。体外抗增殖试验筛选并确认，14种化合物对MOLM-13细胞表现出高度抑制活性，IC值在微摩尔范围内。其中，化合物24对MOLM-13细胞表现出最佳的抗增殖活性，IC值为0.034 μM，与阳性药物（BAY1251152，IC = 0.031 μM）相当。体外激酶抑制试验结果表明，化合物24对CDK9具有相当的抑制活性，IC值为5.5 nM，对其他细胞周期蛋白依赖性激酶具有较弱的抑制活性。进一步的细胞机制分析表明，24影响CDK9信号通路，诱导细胞凋亡并使细胞周期停滞在G2/M期。最后，对化合物24进行了分子对接、分子动力学模拟和药物代谢及毒性预测的进一步研究。总体而言，化合物24在治疗急性髓系白血病方面值得进一步的结构优化和开发。
