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Discovery of JN122, a Spiroindoline-Containing Molecule that Inhibits MDM2/p53 Protein-Protein Interaction and Exerts Robust In Vivo Antitumor Efficacy

文献类型：期刊论文

作者Cheng, Jing2,5; Yan, Ziqin2; Jiang, Kailong1; Liu, Chen2,3; Xu, Dehua1,4; Lyu, Xilin2; Hu, Xiaobei1; Zhang, Shiyan2,5; Zhou, Yubo1,2; Li, Jia1,2,4
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-12-07
卷号66期号:24页码:16991-17025
ISSN号0022-2623
DOI10.1021/acs.jmedchem.3c01815
通讯作者Zhou, Yubo(yjzhao@simm.ac.cn) ; Li, Jia(jli@simm.ac.cn) ; Zhao, Yujun(ybzhou@simm.ac.cn)
英文摘要MDM2 and MDM4 cooperatively and negatively regulate p53, while this pathway is often hijacked by cancer cells in favor of their survival. Blocking MDM2/p53 interaction with small-molecule inhibitors liberates p53 from MDM2 mediated degradation, which is an attractive strategy for drug discovery. We reported herein structure-based discovery of highly potent spiroindoline-containing MDM2 inhibitor (-)60 (JN122), which also exhibited moderate activities against MDM4/p53 interactions. In a panel of cancer cell lines harboring wild type p53, (-)60 efficiently promoted activation of p53 and its target genes, inhibited cell cycle progression, and induced cell apoptosis. Interestingly, (-)60 also promoted degradation of MDM4. More importantly, (-)60 exhibited good PK properties and exerted robust antitumor efficacies in a systemic mouse xenograft model of MOLM-13. Taken together, our study showcases a class of potent MDM2 inhibitors featuring a novel spiro-indoline scaffold, which is promising for future development targeting cancer cells with wild-type p53.
WOS关键词FLUORESCENCE POLARIZATION ASSAY ; DOUBLE MINUTE 2 ; P53 PATHWAY ; PRACTICAL SYNTHESIS ; CLINICAL-TRIALS ; HIGHLY POTENT ; MDMX ; DESIGN ; ACTIVATION ; INACTIVATION
资助项目National Natural Science Foundation of China[82273759] ; National Natural Science Foundation of China[82073682] ; National Natural Science Foundation of China[81872724] ; National Natural Science Foundation of China[22ZR1474500] ; Science and Technology Commission of Shanghai Municipality[2023000003] ; Science and Technology Commission of Shanghai Municipality[2019B090904008] ; Guangdong High-level New RD Institute[2021B0909050003] ; Guangdong High-level Innovative Research Institute[2021GXRC069] ; Jinan Innovation Team Project[SIMM0320231008] ; State Key Laboratory of Drug Research at Shanghai Institute of Materia Medica
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001134061000001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/308514]  
专题新药研究国家重点实验室
通讯作者Zhou, Yubo; Li, Jia; Zhao, Yujun
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Zhongshan Inst Drug Discovery, Zhongshan 528400, Peoples R China
2.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
4.Dalian Univ Technol, Sch Life & Pharmaceut Sci, Panjin 124000, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
6.Zhengzhou Univ, Sch Pharmaceut Sci, Zhengzhou 450001, Peoples R China
7.Shandong Acad Pharmaceut Sci, Shandong Prov Key Lab Biopharmaceut, Jinan 250101, Peoples R China
推荐引用方式
GB/T 7714		 Cheng, Jing,Yan, Ziqin,Jiang, Kailong,et al. Discovery of JN122, a Spiroindoline-Containing Molecule that Inhibits MDM2/p53 Protein-Protein Interaction and Exerts Robust In Vivo Antitumor Efficacy[J]. JOURNAL OF MEDICINAL CHEMISTRY,2023,66(24):16991-17025.
APA Cheng, Jing.,Yan, Ziqin.,Jiang, Kailong.,Liu, Chen.,Xu, Dehua.,...&Zhao, Yujun.(2023).Discovery of JN122, a Spiroindoline-Containing Molecule that Inhibits MDM2/p53 Protein-Protein Interaction and Exerts Robust In Vivo Antitumor Efficacy.JOURNAL OF MEDICINAL CHEMISTRY,66(24),16991-17025.
MLA Cheng, Jing,et al."Discovery of JN122, a Spiroindoline-Containing Molecule that Inhibits MDM2/p53 Protein-Protein Interaction and Exerts Robust In Vivo Antitumor Efficacy".JOURNAL OF MEDICINAL CHEMISTRY 66.24(2023):16991-17025.

入库方式： OAI收割

来源：上海药物研究所

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