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.
Copyright © 2021 Elsevier Masson SAS. All rights reserved.
MeSH terms
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Cell Line, Tumor
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Cell Movement / drug effects
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Dose-Response Relationship, Drug
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Drug Development*
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Humans
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Molecular Docking Simulation
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Molecular Structure
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Structure-Activity Relationship
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Sulfhydryl Compounds / chemical synthesis
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Sulfhydryl Compounds / chemistry
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Sulfhydryl Compounds / pharmacology*
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Triazoles / chemical synthesis
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Triazoles / chemistry
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Triazoles / pharmacology*
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Ubiquitin-Conjugating Enzymes / antagonists & inhibitors*
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Ubiquitin-Conjugating Enzymes / genetics
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Ubiquitin-Conjugating Enzymes / metabolism
Substances
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DCUN1D1 protein, human
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Enzyme Inhibitors
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Intracellular Signaling Peptides and Proteins
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Sulfhydryl Compounds
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Triazoles
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Ubiquitin-Conjugating Enzymes
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UBE2M protein, human