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 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.