2. Academic Validation
  3. Discovery of candesartan cilexetic as a novel neddylation inhibitor for suppressing tumor growth

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

  • Eur J Med Chem. 2020 Jan 1:185:111848. doi: 10.1016/j.ejmech.2019.111848.
Shuaishuai Ni 1,  Xin Chen 2,  Qing Yu 3,  Yixiang Xu 2,  Zhiguo Hu 4,  Junqian Zhang 1,  Wenjuan Zhang 1,  Baoli Li 2,  Xi Yang 1,  Fei Mao 2,  Jing Huang 5,  Yi Sun 3,  Jian Li 6,  Lijun Jia 7
Affiliations

Affiliations

  • 1 Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
  • 2 State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, China.
  • 3 Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 30029, China.
  • 4 State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 201210, China.
  • 5 Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 6 State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, China. Electronic address: jianli@ecust.edu.cn.
  • 7 Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China. Electronic address: ljjia@shutcm.edu.cn.
PMID: 31732254 DOI: 10.1016/j.ejmech.2019.111848
Abstract

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 cullin1 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.

Keywords

Candesartan cilexetic; Drug repurposing; NAE inhibitor; Neddylation.

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