2. Academic Validation
  3. Development of novel benzimidazole-derived neddylation inhibitors for suppressing tumor growth invitro and invivo

Development of novel benzimidazole-derived neddylation inhibitors for suppressing tumor growth invitro and invivo

  • Eur J Med Chem. 2021 Jan 15:210:112964. doi: 10.1016/j.ejmech.2020.112964.
Xin Chen 1,  Xi Yang 2,  Fei Mao 1,  Jinlian Wei 1,  Yixiang Xu 1,  Baoli Li 1,  Jin Zhu 1,  Shuaishuai Ni 3,  Lijun Jia 4,  Jian Li 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, 130 Mei Long Road, Shanghai, 200237, China.
  • 2 Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
  • 3 Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China. Electronic address: nss1106@126.com.
  • 4 Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China. Electronic address: ljjia@shutcm.edu.cn.
  • 5 State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, 130 Mei Long Road, Shanghai, 200237, China; College of Pharmacy and Chemistry, Dali University, 5 Xue Ren Road, Dali, Yunnan, 671000, China; Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, 130 Mei Long Road, Shanghai, 200237, China. Electronic address: jianli@ecust.edu.cn.
PMID: 33129593 DOI: 10.1016/j.ejmech.2020.112964
Abstract

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 μM vs 16.43 μM), 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.

Keywords

Anticancer; Benzimidazole-derived inhibitor; Neddylation; cullin1-Nedd8.

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