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.

中文翻译：

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发现 1,2,4-三唑-3-硫酮衍生物作为病理性心脏纤维化和重塑的有效和选择性 DCN1 抑制剂


DCN1是neddylation过程中关键的co-E3连接酶，在许多疾病中过度激活，如癌症、心力衰竭以及纤维化疾病，已被视为药物开发的新靶点。在此，我们设计并合成了一类新的基于 1,2,4-三唑-3-硫酮的 DCN1 抑制剂，其基于高通量筛选中鉴定的命中HD1 ，并通过大量结构-活性-关系 (SAR) 探索进行优化。 HD2 (IC ₅₀ = 2.96 nM) 最终被鉴定出来，是一种高效、选择性的 DCN1 抑制剂，具有良好的 PK 特性和低毒性。令人惊讶的是， HD2在体外有效缓解Ang II/TGFβ诱导的心脏成纤维细胞活化，并在体内减少ISO诱导的心脏纤维化和重构，这与抑制cullin 3 neddylation及其底物Nrf2积累有关。我们的研究结果揭示了一种新型的基于 1,2,4-三唑-3-硫酮的衍生物HD2 ，它被认为是一种有前途的针对 DCN1 的先导化合物，用于治疗心脏纤维化和重塑。