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Development of phenyltriazole thiol-based derivatives as highly potent inhibitors of DCN1-UBC12 interaction
Wenjuan Zhou1, Chenhao Xu2, Guanjun Dong2
1State 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.
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.
Insights
Researchers identified SK-464, a novel compound targeting Defective in cullin neddylation 1 (DCN1) interaction. This compound suppressed cancer cell migration and invasion, showing potential as a lead therapeutic agent.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Defective in cullin neddylation 1 (DCN1) acts as a crucial co-E3 ligase in cullin neddylation.
- Aberrant DCN1 expression is linked to the pathogenesis of various cancers.
Purpose of the Study:
- To identify and develop novel small molecules that inhibit DCN1-UBC12 interaction.
- To evaluate the therapeutic potential of these inhibitors in DCN1-overexpressing cancer cells.
Main Methods:
- High-throughput screening to identify initial hit compounds.
- Structure-based drug design for lead optimization.
- In vitro biochemical assays to assess DCN1-UBC12 binding.
- Cell-based assays to evaluate cellular DCN1 engagement, cullin3 neddylation, and cancer cell migration/invasion.
Main Results:
- A novel phenyltriazole thiol compound (5a) was identified with an IC50 of 0.95 μM against DCN1-UBC12 interaction.
- Structure-based optimization yielded SK-464, a potent inhibitor with an IC50 of 26 nM.
- SK-464 demonstrated direct binding to DCN1 in vitro, engaged cellular DCN1, and suppressed cullin3 neddylation.
- SK-464 effectively hindered the migration and invasion of DCN1-overexpressing squamous carcinoma cell lines (KYSE70 and H2170).
Conclusions:
- SK-464 is a potent and selective inhibitor of DCN1-UBC12 interaction.
- SK-464 exhibits anti-migratory and anti-invasive properties in relevant cancer models.
- SK-464 represents a promising lead compound for the development of novel cancer therapeutics targeting DCN1.
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