lancet-header

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 These preprints are early stage research papers that have not been peer-reviewed.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decision making and should not be presented to a lay audience without highlighting that they are preliminary and have not been peer-reviewed.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 preprints@lancet.com.

Discovery of Candesartan Cilexetic as a Novel Neddylation Inhibitor for Suppressing Tumor Growth

57 Pages Posted: 30 Sep 2019

See all articles by Shuaishuai Ni

Shuaishuai Ni

Shanghai University of Traditional Chinese Medicine - Cancer Institute

Xin Chen

East China University of Science and Technology (ECUST) - State Key Laboratory of Bioreactor Engineering

Qing Yu

Zhejiang University - Institute of Translational Medicine

Yixiang Xu

East China University of Science and Technology (ECUST) - State Key Laboratory of Bioreactor Engineering

Zhiguo Hu

Chinese Academy of Sciences (CAS) - CAS Center for Excellence in Molecular Cell Science

Junqian Zhang

Shanghai University of Traditional Chinese Medicine - Cancer Institute

Wenjuan Zhang

Shanghai University of Traditional Chinese Medicine - Cancer Institute; Fudan University - Shanghai Cancer Center (FUSCC)

Baoli Li

East China University of Science and Technology (ECUST) - State Key Laboratory of Bioreactor Engineering

Xi Yang

Shanghai University of Traditional Chinese Medicine - Cancer Institute

Fei Mao

East China University of Science and Technology (ECUST) - State Key Laboratory of Bioreactor Engineering

Jing Huang

Shanghai Jiao Tong University (SJTU) - Shanghai Ninth People’s Hospital

Yi Sun

Zhejiang University - Institute of Translational Medicine; University of Michigan at Ann Arbor - Division of Radiation and Cancer Biology

Jian Li

East China University of Science and Technology (ECUST) - State Key Laboratory of Bioreactor Engineering

Lijun Jia

Shanghai Jiao Tong University (SJTU) - Department of Oncology; Shanghai University of Traditional Chinese Medicine - Cancer Institute

More...

Abstract

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

Ni, Shuaishuai and Chen, Xin and Yu, Qing and Xu, Yixiang and Hu, Zhiguo and Zhang, Junqian and Zhang, Wenjuan and Li, Baoli and Yang, Xi and Mao, Fei and Huang, Jing and Sun, Yi and Li, Jian and Jia, Lijun, Discovery of Candesartan Cilexetic as a Novel Neddylation Inhibitor for Suppressing Tumor Growth (September 20, 2019). Available at SSRN: https://ssrn.com/abstract=3457385 or http://dx.doi.org/10.2139/ssrn.3457385

Shuaishuai Ni

Shanghai University of Traditional Chinese Medicine - Cancer Institute

Shanghai, 200032
China

Xin Chen

East China University of Science and Technology (ECUST) - State Key Laboratory of Bioreactor Engineering

Shanghai, 200237
China

Qing Yu

Zhejiang University - Institute of Translational Medicine

China

Yixiang Xu

East China University of Science and Technology (ECUST) - State Key Laboratory of Bioreactor Engineering

Shanghai, 200237
China

Zhiguo Hu

Chinese Academy of Sciences (CAS) - CAS Center for Excellence in Molecular Cell Science

320 Yue Yang Road
Shanghai, 200031
China

Junqian Zhang

Shanghai University of Traditional Chinese Medicine - Cancer Institute

Shanghai, 200032
China

Wenjuan Zhang

Shanghai University of Traditional Chinese Medicine - Cancer Institute

Shanghai, 200032
China

Fudan University - Shanghai Cancer Center (FUSCC)

1207 Rm., 2# Bldg., 270 Dong An Rd.
Shanghai, 200032
China

Baoli Li

East China University of Science and Technology (ECUST) - State Key Laboratory of Bioreactor Engineering

Shanghai, 200237
China

Xi Yang

Shanghai University of Traditional Chinese Medicine - Cancer Institute

Shanghai, 200032
China

Fei Mao

East China University of Science and Technology (ECUST) - State Key Laboratory of Bioreactor Engineering

Shanghai, 200237
China

Jing Huang

Shanghai Jiao Tong University (SJTU) - Shanghai Ninth People’s Hospital

Shanghai
China

Yi Sun

Zhejiang University - Institute of Translational Medicine ( email )

China

University of Michigan at Ann Arbor - Division of Radiation and Cancer Biology ( email )

1500 E Medical Center Dr.
UH B2C490
Ann Arbor, 48109-5010
United States

Jian Li

East China University of Science and Technology (ECUST) - State Key Laboratory of Bioreactor Engineering ( email )

Shanghai, 200237
China

Lijun Jia (Contact Author)

Shanghai Jiao Tong University (SJTU) - Department of Oncology

Shanghai
China

Shanghai University of Traditional Chinese Medicine - Cancer Institute ( email )

Shanghai, 200032
China

Click here to go to TheLancet.com

Paper statistics

Abstract Views
201
Downloads
5
PlumX Metrics