Discovery of 1,2,4-Triazole-3-thione Derivatives as Potent and Selective DCN1 Inhibitors for Pathological Cardiac Fibrosis and Remodeling

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 <b>HD1</b> identified from high-throughput screening and optimized through numerous structure-activity-relationship (SAR) explorations. <b>HD2</b> (IC₅₀= 2.96 nM) was finally identified and represented a highly potent and selective DCN1 inhibitor with favorable PK properties and low toxicity. Amazingly, <b>HD2</b> effectively relieved Ang II/TGFβ-induced cardiac fibroblast activation <i>in vitro</i>, and reduced ISO-induced cardiac fibrosis as well as remodeling <i>in vivo</i>, 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 <b>HD2</b>, which can be recognized as a promising lead compound targeting DCN1 for cardiac fibrosis and remodeling.