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Updated: Jan 28, 2026

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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Development of Highly Potent, Selective, and Cellular Active Triazolo[1,5- a]pyrimidine-Based Inhibitors Targeting

Shuai Wang1,2,3, Lijie Zhao1,2,3, Xiao-Jing Shi1,2,3

  • 1School of Pharmaceutical Sciences and Institute of Drug Discovery & Development , Zhengzhou University , Zhengzhou 450001 , China.

Journal of Medicinal Chemistry
|February 27, 2019
PubMed

Insights

Researchers developed novel triazolo[1,5- a]pyrimidine inhibitors targeting the DCN1-UBC12 interaction. Compound WS-383 selectively inhibits Cul3/1 neddylation, showing therapeutic potential for diseases linked to cullin-RING ubiquitin ligase dysfunction.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • Cullin-RING ubiquitin ligases (CRLs) regulate ~20% of cellular protein degradation and are implicated in human diseases.
  • Targeting CRLs is an emerging therapeutic strategy for various diseases.

Purpose of the Study:

  • To discover and optimize novel inhibitors targeting the DCN1-UBC12 interaction.
  • To evaluate the therapeutic potential of these inhibitors for diseases involving CRL dysfunction.

Main Methods:

  • Hit compound discovery from an in-house library.
  • Structure-based optimization of triazolo[1,5- a]pyrimidine derivatives.
  • Biochemical assays to determine inhibitory activity (IC50) and selectivity.
  • Cellular assays to assess target engagement and downstream effects.

Main Results:

  • Identified WS-383, a potent and reversible inhibitor of the DCN1-UBC12 interaction (IC50 = 11 nM).
  • WS-383 demonstrated selectivity over other kinases and inhibited Cul3/1 neddylation selectively.
  • Compound showed cellular target engagement with DCN1 and induced accumulation of p21, p27, and NRF2.

Conclusions:

  • Targeting the DCN1-UBC12 interaction is a viable strategy for selective Cul3/1 neddylation inhibition.
  • WS-383 and similar compounds hold therapeutic potential for diseases associated with dysregulated Cul3/1 activity.

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