文献类型：期刊文献

英文题名：Development of novel benzimidazole-derived neddylation inhibitors for suppressing tumor growth in vitro and in vivo

作者：Chen, Xin[1];Yang, Xi[2];Mao, Fei[1];Wei, Jinlian[1];Xu, Yixiang[1];Li, Baoli[1];Zhu, Jin[1];Ni, Shuaishuai[2];Jia, Lijun[2];Li, Jian[1,3,4]

机构：[1]East China Univ Sci & Technol, State Key Lab Bioreactor Engn, Shanghai Key Lab New Drug Design, 130 Mei Long Rd, Shanghai 200237, Peoples R China;[2]Shanghai Univ Tradit Chinese Med, Longhua Hosp, Canc Inst, Shanghai 200032, Peoples R China;[3]Dali Univ, Coll Pharm & Chem, 5 Xue Ren Rd, Dali 671000, Yunnan, Peoples R China;[4]East China Univ Sci & Technol, Frontiers Sci Ctr Materiobiol & Dynam Chem, 130 Mei Long Rd, Shanghai 200237, Peoples R China

年份：2021

卷号：210

外文期刊名：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000604903800017)】；

基金：This workwas supported by the Chinese Minister of Science and Technology grant (2016YFA0501800), the National Natural Science Foundation of China (Grants 81872747, 21702061, 81625018, 81820108022), the Innovative Research Team of High-level Local Universities in Shanghai, the National Special Fund for State Key Laboratory of Bioreactor Engineering (2060204), and the National Key R&D Programof China (2017YFB0202600). Innovation Program of Shanghai Municipal Education Commission (2019-01-07-00-10-E00056), Program of Shanghai Academic/Technology Research Leader (18XD1403800).

语种：英文

外文关键词：Neddylation; cullin1-Nedd8; Benzimidazole-derived inhibitor; Anticancer

摘要：Ubiquitin-like protein neddylation is overactivated in various human cancers and correlates with disease progression, and targeting this pathway represents a valuable therapeutic strategy. Our previous work disclosed an antihypertensive agent, candesartan cilexetic (CDC), serves as a novel neddylation inhibitor for suppressing tumor growth by targeting Nedd8-activating enzyme (NAE). In this study, 42 benzimidazole derivatives were designed and synthesized based on lead compound CDC to improve the neddylation inhibition and anticancer efficacy. Optimal benzimidazole-derived 35 displayed superior neddylation inhibition in enzyme assay compared to CDC (IC50 = 5.51 mu M vs 16.43 mu M), along with promising target inhibitory activity and killing selectivity in cancer cell. The results of cellular mechanism research combined with tumor growth suppression in human lung cancer cell A549 in vivo, accompanied with docking model, revealed that 35 has the potential to be developed as a promising neddylation inhibitor for anticancer therapy. (C) 2020 Elsevier Masson SAS. All rights reserved.