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Structure-Based Discovery of MDM2/4 Dual Inhibitors that Exert Antitumor Activities against MDM4-Overexpressing Cancer Cells

文献类型：期刊论文

作者Zhang, Shiyan5,6,7; Yan, Ziqin6,7; Li, Yafang4,6,7; Gong, Yang3,6,7; Lyu, Xilin6,7; Lou, Jianfeng5,6,7; Zhang, Daizhou2; Meng, Xiangjing2; Zhao, Yujun1,2,3,5,6,7
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2022-04-28
卷号65期号:8页码:6207-6230
ISSN号0022-2623
DOI10.1021/acs.jmedchem.2c00095
通讯作者Meng, Xiangjing(fredamxj@163.com) ; Zhao, Yujun(yjzhao@simm.ac.cn)
英文摘要Despite recent clinical progress in peptide-based dual inhibitors of MDM2/4, small-molecule ones with robust antitumor activities remain challenging. To tackle this issue, 31 (YL93) was structure-based designed and synthesized, which had MDM2/4 binding Ki values of 1.1 and 642 nM, respectively. In three MDM4-overexpressing cancer cell lines harboring wild-type p53, 31 shows improved cell growth inhibition activities compared to RG7388, an MDM2-selective inhibitor in late-stage clinical trials. Mechanistic studies show that 31 increased cellular protein levels of p53 and p21 and upregulated the expression of p53- targeted genes in RKO cells with MDM4 amplification. In addition, 31 induced cell-cycle arrest and apoptosis in western blot and flow cytometry assays. Taken together, dual inhibition of MDM2/4 by 31 elicited stronger antitumor activities in vitro compared to selective MDM2 inhibitors in wild-type p53 and MDM4-overexpressing cancer cells
WOS关键词FLUORESCENCE POLARIZATION ASSAY ; P53 PATHWAY ; MDMX ; POTENT ; ACTIVATION ; OPTIMIZATION ; ANTAGONISTS ; BINDING ; DESIGN ; ROLES
资助项目National Natural Science Foundation of China[82073682] ; National Natural Science Foundation of China[81872724] ; Jinan Innovation Team Project[2021GXRC069] ; Science and Technology Commission of Shanghai Municipality[18431907100] ; Science and Technology Commission of Shanghai Municipality[22ZR1474500]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000797573100022
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/301116]  
专题新药研究国家重点实验室
通讯作者Meng, Xiangjing; Zhao, Yujun
作者单位1.Zhengzhou Univ, Sch Pharmaceut Sci, Zhengzhou 450001, Peoples R China
2.Shandong Acad Pharmaceut Sci, Shandong Prov Key Lab Biopharmaceut, Jinan 250101, Peoples R China
3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
4.Univ Sci & Technol China, Nano Sci & Technol Inst, Suzhou 215123, Jiangsu, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
6.Chinese Acad Sci, Small Mol Drug Res Ctr, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
7.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Shiyan,Yan, Ziqin,Li, Yafang,et al. Structure-Based Discovery of MDM2/4 Dual Inhibitors that Exert Antitumor Activities against MDM4-Overexpressing Cancer Cells[J]. JOURNAL OF MEDICINAL CHEMISTRY,2022,65(8):6207-6230.
APA Zhang, Shiyan.,Yan, Ziqin.,Li, Yafang.,Gong, Yang.,Lyu, Xilin.,...&Zhao, Yujun.(2022).Structure-Based Discovery of MDM2/4 Dual Inhibitors that Exert Antitumor Activities against MDM4-Overexpressing Cancer Cells.JOURNAL OF MEDICINAL CHEMISTRY,65(8),6207-6230.
MLA Zhang, Shiyan,et al."Structure-Based Discovery of MDM2/4 Dual Inhibitors that Exert Antitumor Activities against MDM4-Overexpressing Cancer Cells".JOURNAL OF MEDICINAL CHEMISTRY 65.8(2022):6207-6230.

入库方式： OAI收割

来源：上海药物研究所

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