Discovery of novel CDK9 inhibitor with tridentate ligand: Design, synthesis and biological evaluation
文献类型：期刊论文
| 作者 | Zhong, Ye4; Xu, Jing2,3; Ding, Shaoyue4; Cao, Huiying2; Zhang, Yufei2; Hu, Baichun4; Han, Shucheng4; Yang, Huali4; Cheng, Maosheng4; Li, Jia1,2,3
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| 刊名 | BIOORGANIC CHEMISTRY
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| 出版日期 | 2024-09-01 |
| 卷号 | 150页码:12 |
| 关键词 | CDK9 Inhibitor Colorectal cancer Apoptosis Tridentate ligand |
| ISSN号 | 0045-2068 |
| DOI | 10.1016/j.bioorg.2024.107550 |
| 通讯作者 | Zhong, Ye() |
| 英文摘要 | Cyclin-dependent kinase 9 (CDK9) plays a role in transcriptional regulation, which had become an attractive target for discovery of antitumor agent. In this work, beyond traditional CDK9 inhibitor with bidentate ligands in ATP binding domain, a series of novel CDK9 inhibitor with tridentate ligand were designed and synthesized. Surprisingly, this unique tridentate ligand structure endows better CDK9 inhibition selectivity compared to other CDK subtypes, and the lead candidate compound Z4-7a showed effective proliferation inhibition in HCT116 cells with acceptable pharmacokinetic properties. Research on the mechanism indicated that Z4-7a 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. In brief, introduction of tridentate ligand might work as a promising strategy for the development of novel selective CDK9 inhibitor. |
| WOS关键词 | KB-0742 ; POTENT |
| 资助项目 | National Natural Science Foundation of China[22177079] ; National Natural Science Foundation of China[81903682] ; Shanghai City Science and Technology Commission[19YF1410200] ; Taishan Scholar Foundation of Shandong Province[tstp0648] ; Program for Liaoning Innovative Talents in University[LR2017043] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001257782000001 |
| 出版者 | ACADEMIC PRESS INC ELSEVIER SCIENCE |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/312011]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Zhong, Ye |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Stake Key Lab Chem Biol, Shanghai 201203, Peoples R China 2.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Peoples R China 3.Shenyang Pharmaceut Univ, Dept Pharmacol, 103 Wenhua Rd, Shenyang 110016, Peoples R China 4.Shenyang Pharmaceut Univ, Key Lab Struct Based Drug Design & Discovery, Minist Educ, Sch Pharmaceut Engn, Shenyang 110016, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhong, Ye,Xu, Jing,Ding, Shaoyue,et al. Discovery of novel CDK9 inhibitor with tridentate ligand: Design, synthesis and biological evaluation[J]. BIOORGANIC CHEMISTRY,2024,150:12. |
| APA | Zhong, Ye.,Xu, Jing.,Ding, Shaoyue.,Cao, Huiying.,Zhang, Yufei.,...&Liu, Yang.(2024).Discovery of novel CDK9 inhibitor with tridentate ligand: Design, synthesis and biological evaluation.BIOORGANIC CHEMISTRY,150,12. |
| MLA | Zhong, Ye,et al."Discovery of novel CDK9 inhibitor with tridentate ligand: Design, synthesis and biological evaluation".BIOORGANIC CHEMISTRY 150(2024):12. |
入库方式： OAI收割
来源：上海药物研究所
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