Discovery of N-(3,4-Dimethylphenyl)-4-(4-isobutyrylphenyl)-2,3,3a,4,5,9b-hexahydrofuro3,2-cquinoline-8-sulfonamide as a Potent Dual MDM2/XIAP Inhibitor

Zhongzhi  Wu; Lubing  Gu; Sicheng  ZhangTao  LiuPradeep B.  LukkaBernd  MeibohmJohn C.  BollingerMuxiang  ZhouWei  Li

首页> 外文期刊>Journal of Medicinal Chemistry >Discovery of N-(3,4-Dimethylphenyl)-4-(4-isobutyrylphenyl)-2,3,3a,4,5,9b-hexahydrofuro3,2-cquinoline-8-sulfonamide as a Potent Dual MDM2/XIAP Inhibitor

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Discovery of N-(3,4-Dimethylphenyl)-4-(4-isobutyrylphenyl)-2,3,3a,4,5,9b-hexahydrofuro3,2-cquinoline-8-sulfonamide as a Potent Dual MDM2/XIAP Inhibitor

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Murine double minute 2 (MDM2) and X-linked inhibitor of apoptosis protein (XIAP) are important cell survival proteins in tumor cells. As a dual MDM2/XIAP inhibitor reported previously, compound MX69 has low potency with an IC_(50) value of 7.5 μM against an acute lymphoblastic leukemia cell line EU-1. Herein, we report the structural optimization based on the MX69 scaffold, leading to the discovery of a 25-fold more potent analogue 14 (IC_(50) = 0.3 μM against EU-1). We demonstrate that 14 maintains its mode of action by dual targeting of MDM2 and XIAP through inducing MDM2 protein degradation and inhibiting XIAP mRNA translation, respectively, which resulted in cancer cell growth inhibition and cell death. The results strongly suggest that the scaffold based on 14 is promising for further optimization to develop a new therapeutic agent for leukemia and possibly other cancers where MDM2 and XIAP are dysregulated.

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《Journal of Medicinal Chemistry》 |2021年第4期|1930-1950|共21页
作者
Zhongzhi Wu; Lubing Gu; Sicheng ZhangTao LiuPradeep B. LukkaBernd MeibohmJohn C. BollingerMuxiang ZhouWei Li;
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Department of Structural Biology, Biomolecular X-Ray Crystallography Center;

Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center;

Department of Pediatrics and Aflac Cancer and Blood Disorders Center, Emory University School of Medicine;

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正文语种英语
中图分类药学;
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1. Discovery of N-(3,4-Dimethylphenyl)-4-(4-isobutyrylphenyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline-8-sulfonamide as a Potent Dual MDM2/XIAP Inhibitor [J] . Zhongzhi Wu, Lubing Gu, Sicheng Zhang, Journal of Medicinal Chemistry . 2021,第4期

机译：发现N-（3,4-二甲基苯基）-4-（4-异丁酰基）-2,3,3a，4,5,9b-六氢呋喃[3,2-c]喹啉-8-磺酰胺，为有效的双mdm2 / XIAP抑制剂
2. Discovery of N-((3S,4S)-4-(3,4-Difluorophenyl)piperidin-3-yl)-2-fluoro-4-(1-methyl-1H-pyrazol-5-yl)benzamide (Hu7691), a Potent and Selective Akt Inhibitor That Enables Decrease of Cutaneous Toxicity [J] . Che Jinxin, Dai Xiaoyang, Gao JianSheng HaichaoZhan WenhuLu YangLi DanGao ZizhengJin ZegaoChen BinhuiLuo PeihuaYang BoHu YongzhouHe QiaojunWeng QinjieDong Xiaowu Journal of Medicinal Chemistry . 2021,第16期

机译：Discovery of N-((3S,4S)-4-(3,4-Difluorophenyl)piperidin-3-yl)-2-fluoro-4-(1-methyl-1H-pyrazol-5-yl)benzamide (Hu7691), a Potent and Selective Akt Inhibitor That Enables Decrease of Cutaneous Toxicity
3. 8-Methyl-4-phenyl-2,3,3a,4,5,9b-hexa-hydro-furo[3,2-c]quinoline [J] . Lu P., Lian C., Zhu Y. Acta Crystallographica Section E: Crystallographic Communications . 2010,第1期

机译：8-甲基-4-苯基-2,3,3a，4,5,9b-六氢呋喃[3,2-c]喹啉
4. 8-Methyl-4-phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline [O] . Pingping Lu, Chaomei Lian, Yulin Zhu 2010

机译：8-甲基-4-苯基-2,3,3a，4,5,9b-六六氢呋喃并[3,2-c]喹啉

Discovery of N-(3,4-Dimethylphenyl)-4-(4-isobutyrylphenyl)-2,3,3a,4,5,9b-hexahydrofuro3,2-cquinoline-8-sulfonamide as a Potent Dual MDM2/XIAP Inhibitor

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