2. Academic Validation
  3. Development of phenyltriazole thiol-based derivatives as highly potent inhibitors of DCN1-UBC12 interaction

Development of phenyltriazole thiol-based derivatives as highly potent inhibitors of DCN1-UBC12 interaction

  • Eur J Med Chem. 2021 May 5:217:113326. doi: 10.1016/j.ejmech.2021.113326.
Wenjuan Zhou 1,  Chenhao Xu 2,  Guanjun Dong 2,  Hui Qiao 2,  Jing Yang 2,  Hongmin Liu 2,  Lina Ding 3,  Kai Sun 4,  Wen Zhao 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, PR China; Department of Pathology, Oslo University Hospital, Faculty of Medicine, University of Oslo, Oslo, 0379, Norway.
  • 2 State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, PR China.
  • 3 State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, PR China. Electronic address: dinglina123@126.com.
  • 4 State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, PR China. Electronic address: kaisun@zzu.edu.cn.
  • 5 State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, PR China. Electronic address: zhaowen@zzu.edu.cn.
PMID: 33756127 DOI: 10.1016/j.ejmech.2021.113326
Abstract

Defective in cullin neddylation 1(DCN1) is a co-E3 Ligase that is important for cullin neddylation. Dysregulation of DCN1 highly correlates with the development of various cancers. Herein, from the initial high-throughput screening, a novel hit compound 5a containing a phenyltriazole thiol core (IC50 value of 0.95 μM for DCN1-UBC12 interaction) was discovered. Further structure-based optimization leads to the development of SK-464 (IC50 value of 26 nM). We found that SK-464 not only directly bound to DCN1 in vitro, but also engaged cellular DCN1, suppressed the neddylation of cullin3, and hindered the migration and invasion of two DCN1-overexpressed squamous carcinoma cell lines (KYSE70 and H2170). These findings indicate that SK-464 may be a novel lead compound targeting DCN1-UBC12 interaction.

Keywords

DCN1; Inhibitor; Interaction; Migration; Triazolethiols; UBC12.

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