Chemical discovery of a novel MD2/ADAM17 dual-target inhibitor as a potential therapeutic candidate for saturated fatty acid-induced myocardial inflammatory injury

Background and aims: While the therapeutic promise of anti-inflammatory interventions for obesity-associated cardiomyopathy is well recognized, clinically effective targeted therapies remain to be developed. Here, through systematic anti-inflammatory screening, we elucidated both the therapeutic efficacy and mechanistic basis of a novel indole-substituted acetamide derivative (compound #3) in mitigating obesity-induced cardiomyopathy.

Methods: A high-fat diet (HFD)-induced obese mouse model was used to evaluate the cardioprotective efficacy of compound #3. Integrated in vivo and in vitro studies, including transcriptomics, reverse molecular docking, proteomics, surface plasmon resonance, and kinase activity assays, were conducted to systematically identify molecular targets and elucidate the underlying mechanisms.

Results: Compound #3 attenuated hypertension in HFD-induced obese mice without altering metabolic parameters (body weight, blood glucose, and lipid levels). This cardioprotective effect was attributed to improved cardiac function and anti-inflammatory mechanisms, including the suppression of NF-κB-driven inflammatory injury. Mechanistic studies revealed that compound #3 targeted the L348 residue of ADAM17, disrupting ADAM17-dependent inflammatory signal amplification. This cascade was primarily initiated by the MD2-P38MAPK/JNK-iRhom2 axis. In addition, compound #3 directly bound to MD2, inhibiting palmitic acid (PA)-induced activation of P38MAPK and JNK. This mechanism blocked the initiation of inflammatory responses and further suppressed ADAM17 and cytokine transcription through the P38MAPK-AP1 axis.

Conclusion: Compound #3 exhibits a dual-targeting mechanism by simultaneously inhibiting MD2 and ADAM17, which effectively suppresses both the initiation (via the MD2-P38MAPK/JNK) and amplification (via the P38MAPK/JNK-iRhom2-ADAM17 axis) of inflammatory cascades, highlighting its strong therapeutic promise for treating saturated fatty acid-induced myocardial pathologies.

ADAM17; MAPK; MD2; N-terminus of iRhom2; Obesity cardiomyopathy.