Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 210, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2020.112964
Keywords
Neddylation; cullin1-Nedd8; Benzimidazole-derived inhibitor; Anticancer
Categories
Funding
- Chinese Minister of Science and Technology grant [2016YFA0501800]
- National Natural Science Foundation of China [81872747, 21702061, 81625018, 81820108022]
- Innovative Research Team of High-level Local Universities in Shanghai
- National Special Fund for State Key Laboratory of Bioreactor Engineering [2060204]
- 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]
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The study designed and synthesized 42 benzimidazole derivatives, with optimized compound 35 displaying superior neddylation inhibition and promising selective killing activity in cancer cells, along with potential for tumor growth suppression in human lung cancer cells in vivo.
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.
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