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

Zhongzhi  Wu; Lubing  Gu; Sicheng  Zhang; Tao  Liu; Pradeep B.  Lukka; Bernd  Meibohm; John C.  Bollinger; Muxiang  Zhou; Wei  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-hexahydrofuro[3,2-c]quinoline-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-hexahydrofuro[3,2-c]quinoline-8-sulfonamide as a Potent Dual MDM2/XIAP Inhibitor

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

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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.

机译：小鼠双分钟2（MDM2）和X-连锁凋亡抑制蛋白（XIAP）是肿瘤细胞中重要的细胞存活蛋白。作为之前报道的MDM2/XIAP双抑制剂，化合物MX69对急性淋巴细胞白血病细胞系EU-1的IC_50值为7.5μM，效力较低。在本文中，我们报告了基于MX69支架的结构优化，从而发现了一种25倍更有效的类似物14（IC_50）=0.3μM，与EU-1相比）。我们证明，14分别通过诱导MDM2蛋白降解和抑制XIAP mRNA翻译，通过MDM2和XIAP的双重靶向维持其作用模式，从而导致癌细胞生长抑制和细胞死亡。结果有力地表明，基于14的支架有望进一步优化，以开发一种新的治疗药物，治疗白血病，以及MDM2和XIAP失调的其他癌症。

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来源
《Journal of Medicinal Chemistry》 |2021年第4期|共21页
作者
Zhongzhi Wu; Lubing Gu; Sicheng Zhang; Tao Liu; Pradeep B. Lukka; Bernd Meibohm; John C. Bollinger; Muxiang Zhou; Wei Li;
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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;

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;

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

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

Department of Structural Biology Biomolecular X-Ray Crystallography Center;

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

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

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正文语种 eng
中图分类药学;
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1. Discovery and biological evaluation of N-(3-(7-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-methyl-2-oxo-2H-pyrimido4,5-d1,3oxazin-1 (4H)-yl)phenyl)acrylamide as potent Bruton's tyrosine kinase inhibitors [J] . Meng-zhen Lai, Pei-ran Song, Dou Dou, 中国药理学报：英文版 . 2020,第003期
2. Discovery of N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays [J] . Lombardo LJ, Lee FY, Chen P, Journal of Medicinal Chemistry . 2004,第27期

机译：N-（2-氯-6-甲基苯基）-2-（6-（4-（2-羟乙基）-哌嗪-1-基）-2-甲基嘧啶-4-基氨基）噻唑-5-羧酰胺（BMS）的发现-354825），一种在临床前测定中具有有效抗肿瘤活性的双重Src / Abl激酶抑制剂
3. Synthesis and characterization of N-(4-(4-chlorophenyl)-6-(3,4- dimethylphenyl)pyrimidin-2-yl)-4-(2,6-diphenyl-4-thioxo-2H-1,3,5-oxadiazin-3(4H)-yl)benzenesulfonamide [J] . Rambabu Nunna, Viral B. Modi, Kirti J.Goswami Der Pharma Chemica: journal for medicinal chemistry, pharmaceutical chemistry and computational chemistry . 2012,第1期

机译：N-（4-（4-氯苯基）-6-（3,4-二甲基苯基）嘧啶-2-基）-4-（2,6-二苯基-4-thioxo-2H-1,3， 5-恶二嗪-3（4H）-基）苯磺酰胺
4. Discovery of Dual Inhibitors of MDM2 and XIAP for Cancer Treatment [J] . Gu Lubing, Zhang Hailong, Liu Tao, Cancer Cell . 2016,第4期

机译：发现用于癌症治疗的MDM2和XIAP双重抑制剂
5. Discovery of dual inhibitors of MDM2 and XIAP for cancer treatment [O] . Lubing Gu, Hailong Zhang, Tao Liu, -1

机译：发现用于癌症治疗的MDM2和XIAP双重抑制剂
6. 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-hexahydrofuro[3,2-c]quinoline-8-sulfonamide as a Potent Dual MDM2/XIAP Inhibitor

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