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Identification of a Novel Selective CDK9 Inhibitor for the Treatment of CRC: Design, Synthesis, and Biological Activity Evaluation

文献类型：期刊论文

作者Zhong, Ye5; Xu, Jing3,4; Zhou, Ruochen2; Tang, Li5; Ding, Shaoyue5; Ren, Zhaohui3; Song, Ning1,3; Hu, Baichun5; Yang, Huali5; Sun, Yili1,3
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-03-15
卷号67期号:6页码:4739-4756
ISSN号0022-2623
DOI10.1021/acs.jmedchem.3c02329
通讯作者Sun, Yili(yilisun@simm.ac.cn) ; Cheng, Maosheng(mscheng@syphu.edu.cn) ; Li, Jia(jli@simm.ac.cn) ; Liu, Yang(y.liu@syphu.edu.cn)
英文摘要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.
WOS关键词METASTATIC COLORECTAL-CANCER ; DISCOVERY ; POTENT
资助项目Science and Technology Commission of Shanghai Municipality[22177079] ; Science and Technology Commission of Shanghai Municipality[81903682] ; National Natural Science Foundation of China[19YF1410200] ; Shanghai Science and Technology Committee[LR2017043] ; Liaoning Innovative Talents in University
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001186321200001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/310142]  
专题新药研究国家重点实验室
通讯作者Sun, Yili; Cheng, Maosheng; Li, Jia; Liu, Yang
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
3.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Peoples R China
4.Shenyang Pharmaceut Univ, Dept Pharmacol, Shenyang 110016, Peoples R China
5.Shenyang Pharmaceut Univ, Sch Pharmaceut Engn, Key Lab Struct Based Drug Design & Discovery, Minist Educ, Shenyang 110016, Peoples R China
推荐引用方式
GB/T 7714		 Zhong, Ye,Xu, Jing,Zhou, Ruochen,et al. Identification of a Novel Selective CDK9 Inhibitor for the Treatment of CRC: Design, Synthesis, and Biological Activity Evaluation[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,67(6):4739-4756.
APA Zhong, Ye.,Xu, Jing.,Zhou, Ruochen.,Tang, Li.,Ding, Shaoyue.,...&Liu, Yang.(2024).Identification of a Novel Selective CDK9 Inhibitor for the Treatment of CRC: Design, Synthesis, and Biological Activity Evaluation.JOURNAL OF MEDICINAL CHEMISTRY,67(6),4739-4756.
MLA Zhong, Ye,et al."Identification of a Novel Selective CDK9 Inhibitor for the Treatment of CRC: Design, Synthesis, and Biological Activity Evaluation".JOURNAL OF MEDICINAL CHEMISTRY 67.6(2024):4739-4756.

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来源：上海药物研究所

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