Design, synthesis and bio-evaluation of 2,5-disubstituted thiazole derivatives for potential treatment of acute myeloid leukemia through targeting CDK9
文献类型：期刊论文
| 作者 | Chen, Sumeng2; Huang, Jindi2; Zhang, Shipeng2; Zheng, Xinni1; Chen, Hongming3; Chen, Tie-Gen1; Wang, Ling2 |
| 刊名 | BIOORGANIC CHEMISTRY
 |
| 出版日期 | 2025-06-15 |
| 卷号 | 160页码:16 |
| 关键词 | CDK9 Inhibitor Acute myeloid leukemia Binding mode Cellular mechanism |
| ISSN号 | 0045-2068 |
| DOI | 10.1016/j.bioorg.2025.108436 |
| 通讯作者 | Chen, Hongming(chen_hongming@gzlab.ac.cn) ; Chen, Tie-Gen(chentiegen@simm.ac.cn) ; Wang, Ling(lingwang@scut.edu.cn) |
| 英文摘要 | 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 SyntaLinkerHybrid 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 IC50 values in the micromolar range. Among them, compound 24 displayed the best antiproliferative activity against MOLM-13 cells with an IC50 value of 0.034 mu M, which was comparable to the positive drug (BAY1251152, IC50 = 0.031 mu M). In vitro kinase inhibition assay results demonstrated that compound 24 had considerable inhibitory activity against CDK9 with an IC50 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. |
| WOS关键词 | CYCLIN-DEPENDENT KINASES ; INHIBITOR ; DISCOVERY |
| 资助项目 | Natural Science Foundation of Guangdong Province[2023B1515020042] ; The 100 Talents Program of the Chinese Academy of Sciences, Zhongshan Municipal Bureau of Science and Technology[2021B2014] ; The 100 Talents Program of the Chinese Academy of Sciences, Zhongshan Municipal Bureau of Science and Technology[CXTD2022013] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001480552200001 |
| 出版者 | ACADEMIC PRESS INC ELSEVIER SCIENCE |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/317572]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Chen, Hongming; Chen, Tie-Gen; Wang, Ling |
| 作者单位 | 1.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China 2.South China Univ Technol, Guangdong Prov Engn & Technol Res Ctr Biopharmaceu, Sch Biol & Biol Engn, Guangdong Prov Key Lab Fermentat & Enzyme Engn,Min, Guangzhou 510006, Peoples R China 3.Dept Drug & Vaccine Res, Guangzhou Lab, Guangzhou 510530, Peoples R China |
| 推荐引用方式 GB/T 7714 | Chen, Sumeng,Huang, Jindi,Zhang, Shipeng,et al. Design, synthesis and bio-evaluation of 2,5-disubstituted thiazole derivatives for potential treatment of acute myeloid leukemia through targeting CDK9[J]. BIOORGANIC CHEMISTRY,2025,160:16. |
| APA | Chen, Sumeng.,Huang, Jindi.,Zhang, Shipeng.,Zheng, Xinni.,Chen, Hongming.,...&Wang, Ling.(2025).Design, synthesis and bio-evaluation of 2,5-disubstituted thiazole derivatives for potential treatment of acute myeloid leukemia through targeting CDK9.BIOORGANIC CHEMISTRY,160,16. |
| MLA | Chen, Sumeng,et al."Design, synthesis and bio-evaluation of 2,5-disubstituted thiazole derivatives for potential treatment of acute myeloid leukemia through targeting CDK9".BIOORGANIC CHEMISTRY 160(2025):16. |
入库方式： OAI收割
来源：上海药物研究所
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