Preprints with The Lancet is part of SSRN´s First Look, a place where journals identify content of interest prior to publication. Authors have opted in at submission to The Lancet family of journals to post their preprints on Preprints with The Lancet. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. Preprints available here are not Lancet publications or necessarily under review with a Lancet journal. These preprints are early stage research papers that have not been peer-reviewed. The findings should not be used for clinical or public health decision making and should not be presented to a lay audience without highlighting that they are preliminary and have not been peer-reviewed. For more information on this collaboration, see the comments published in The Lancet about the trial period, and our decision to make this a permanent offering, or visit The Lancet´s FAQ page, and for any feedback please contact firstname.lastname@example.org.
Discovery of Candesartan Cilexetic as a Novel Neddylation Inhibitor for Suppressing Tumor Growth
57 Pages Posted: 30 Sep 2019More...
Background: Protein neddylation is a posttranslational modification of conjugating the neuronal precursor cell-expressed developmentally down-regulated protein 8 (Nedd8) to substrates. The best characterized substrates of neddylation are cullin family members, the essential components of cullin-RING E3 ubiquitin ligases (CRLs). Previous studies have shown that the neddylation pathway is overactivated in various types of human cancers and correlates with the disease progression, whereas pharmacologically targeting this pathway has emerged as an attractive therapeutic strategy.
Methods: To screen the potential neddylation inhibitors for anticancer therapy, the inhibitory effects on neddylation modification of 1331 approved drugs were investigated by an improved enzyme-based assay. Neddylation inhibiting mechanism of hit compound was illuminated by exploring the levels of Nedd8 modification on cullins and the subsequent changes of CRLs substrates in enzyme- and cellular-based assays, along with the molecular docking of hit compound with the target neddylation enzyme. A series of phenotypic experiments, including assays on in vitro cell proliferation, cell cycle arrest and in vivo tumor growth, were applied to investigate the anticancer activities and mechanisms of hit compound.
Findings: An antihypertensive agent candesartan cilexetic (CDC) was identified as a new neddylation inhibitor from 1331 approved drugs based on the strategy of drug repurposing. CDC inhibited neddylation pathway by ATP-competitively suppressing Nedd8-activating enzyme (NAE, E1), which was superior to two representative non-covalent NAE inhibitors, M22 and mitoxantrone. Following with the findings such as apoptotic induction and tumor growth suppression, CDC represents a potential antitumor lead compound with promising neddylation inhibitory activity.
Interpretation: In this study, we identified CDC as a hit compound that blocks the neddylation modification of cullins. Our findings highlighted the potential of developing CDC as a novel neddylation inhibitor.
Funding Statement: This work was supported by the Chinese Minister of Science and Technology grant (2016YFA0501800), National Natural Science Foundation of China (Grant Nos. 81625018, 81820108022), Innovation Program of Shanghai Municipal Education Commission (2019-01-07-00-10-E00056), Program of Shanghai Academic/Technology Research Leader (18XD1403800), National Thirteenth Five-Year Science and Technology Major Special Project for New Drug and Development (2017ZX09304001).
Declaration of Interests: The authors declare no competing financial interests.
Ethics Approval Statement: All experimental protocols were approved by the Animal Experimental Ethics Committee of Longhua Hospital of Shanghai University of Traditional Chinese Medicine.
Keywords: Neddylation, drug repurposing, candesartan cilexetic, NAE inhibitor
Suggested Citation: Suggested Citation