Discovery of candesartan cilexetic as a novel neddylation inhibitor for suppressing tumor growth

摘要

Protein neddylation is a posttranslational modification of conjugating the neuronal precursor cell-expressed developmentally down-regulated protein 8 (Nedd8) to substrates. Our previous work revealed that neddylation pathway is overactivated in various human lung cancers and correlates with the disease progression, whereas pharmacologically targeting this pathway has emerged as an attractive therapeutic strategy. As a follow-up research, 1331 approved drugs were investigated the inhibitory activities of cullinl neddylation for screening the hit compounds via an improved enzyme-based assay. An antihypertensive agent, candesartan cilexetic (CDC), was identified as a novel neddylation inhibitor that ATP-competitively suppressing Nedd8-activating enzyme (NAE, E1) in mechanism, which inhibited the cullins neddylation superior than two representative non-covalent NAE inhibitors, M22 and mitoxantrone. Following with the findings such as apoptotic induction and tumor growth suppression in human lung cancer A549 in vitro and in vivo, CDC represents a potential anticancer lead compound with promising neddylation inhibitory activity. (C) 2019 Elsevier Masson SAS. All rights reserved.