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Discovery of 1,2,4-Triazole-3-thione Derivatives as Potent and Selective DCN1 Inhibitors for Pathological Cardiac
Zhang-Xu He1,2, Ge Gao2, Hui Qiao2
1Pharmacy College, Henan University of Chinese Medicine, 450046 Zhengzhou, PR China.
Abstract:
DCN1, a critical co-E3 ligase during the neddylation process, is overactivated in many diseases, such as cancers, heart failure as well as fibrotic diseases, and has been regarded as a new target for drug development. Herein, we designed and synthesized a new class of 1,2,4-triazole-3-thione-based DCN1 inhibitors based the hit HD1 identified from high-throughput screening and optimized through numerous structure-activity-relationship (SAR) explorations. HD2 (IC50= 2.96 nM) was finally identified and represented a highly potent and selective DCN1 inhibitor with favorable PK properties and low toxicity. Amazingly, HD2 effectively relieved Ang II/TGFβ-induced cardiac fibroblast activation in vitro, and reduced ISO-induced cardiac fibrosis as well as remodeling in vivo, which was linked to the inhibition of cullin 3 neddylation and its substrate Nrf2 accumulation. Our findings unveil a novel 1,2,4-triazole-3-thione-based derivative HD2, which can be recognized as a promising lead compound targeting DCN1 for cardiac fibrosis and remodeling.
Insights
Researchers developed HD2, a potent DCN1 inhibitor targeting cardiac fibrosis. This novel 1,2,4-triazole-3-thione derivative shows promise for treating heart failure and fibrotic diseases by modulating neddylation.
Area of Science:
- Medicinal Chemistry
- Cardiovascular Pharmacology
- Molecular Biology
Background:
- DCN1, a co-E3 ligase in neddylation, is implicated in diseases like cancer and heart failure.
- Overactivated DCN1 presents a therapeutic target for drug development.
Purpose of the Study:
- To design and synthesize novel 1,2,4-triazole-3-thione derivatives as DCN1 inhibitors.
- To evaluate the efficacy of these inhibitors in preclinical models of cardiac fibrosis.
Main Methods:
- High-throughput screening identified initial hit compounds.
- Structure-activity relationship (SAR) studies guided optimization.
- In vitro and in vivo assays assessed DCN1 inhibition and antifibrotic effects.
Main Results:
- HD2 emerged as a highly potent (IC50=2.96 nM) and selective DCN1 inhibitor.
- HD2 demonstrated favorable pharmacokinetic properties and low toxicity.
- HD2 inhibited Ang II/TGFβ-induced cardiac fibroblast activation in vitro and ISO-induced cardiac fibrosis in vivo.
Conclusions:
- HD2 effectively targets DCN1, offering a potential therapeutic strategy for cardiac fibrosis.
- The mechanism involves inhibiting cullin 3 neddylation and Nrf2 accumulation.
- HD2 represents a promising lead compound for DCN1-targeted drug development in cardiovascular diseases.
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