Discovery of the first-in-class FABP/PPAR multiple modulator for the treatment of metabolic dysfunction-associated...

Metabolic dysfunction-associated steatohepatitis (MASH) is a complex metabolic syndrome, and the development of new drugs is urgently needed. Fatty acid binding proteins (FABPs) and peroxisome proliferator-activated receptors (PPARs) play an important role in the regulation of lipid absorption, metabolism and inflammation. Considering the synergistic effect of FABP and PPAR in the regulation of MASH pathophysiology, the development of FABP/PPAR multiple modulators might be a promising anti-MASH strategy. Herein, the first-in-class FABP/PPAR multiple modulators were designed by hybrid resveratrol and PPARs agonist Elafibranor. Among them, the compound 27 was identified as the optimal FABP/PPAR multiple modulator (FABP1 IC₅₀ = 0.65 μM, FABP4 IC₅₀ = 1.08 μM, PPARα EC₅₀ = 9.19 μM, PPARγ EC₅₀ = 2.20 μM, PPARδ EC₅₀ = 1.58 μM). Further MST assay confirmed the direct interaction of compound 27 and FABP1, providing a robust validation of its target specificity. In MASH mice, compound 27 exhibited a better therapeutic effect than clinical candidate obeticholic acid in ameliorating multiple pathological features of MASH. This study reported the successful discovery of the first-in-class FABP/PPAR multiple modulators, which provided preliminary evidence that such multi-target agents have broad medical prospects.