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

Wenjuan Zhou; Chenhao Xu; Guanjun Dong; Hui Qiao; Jing Yang; Hongmin Liu; Lina Ding; Kai Sun; Wen Zhao

doi:10.1016/j.ejmech.2021.113326

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. Epub 2021 Mar 12.

Authors

Wenjuan Zhou¹, Chenhao Xu², Guanjun Dong², Hui Qiao², Jing Yang², Hongmin Liu², Lina Ding³, Kai Sun⁴, Wen Zhao⁵

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.

MeSH terms

Cell Line, Tumor
Cell Movement / drug effects
Dose-Response Relationship, Drug
Drug Development*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism
Molecular Docking Simulation
Molecular Structure
Structure-Activity Relationship
Sulfhydryl Compounds / chemical synthesis
Sulfhydryl Compounds / chemistry
Sulfhydryl Compounds / pharmacology*
Triazoles / chemical synthesis
Triazoles / chemistry
Triazoles / pharmacology*
Ubiquitin-Conjugating Enzymes / antagonists & inhibitors*
Ubiquitin-Conjugating Enzymes / genetics
Ubiquitin-Conjugating Enzymes / metabolism

Substances

DCUN1D1 protein, human
Enzyme Inhibitors
Intracellular Signaling Peptides and Proteins
Sulfhydryl Compounds
Triazoles
Ubiquitin-Conjugating Enzymes
UBE2M protein, human