Discovery of Potent and Selective Imidazo[2,1- <i>b</i> ][1,3,4]thiadiazole-Based MNK1/2 Inhibitors with Significant Efficacy against Diet-Induced Metabolic Dysfunction-Associated Steatotic Liver Disease

Mitogen-activated protein kinase-interacting kinases (MNK1/2) have emerged as promising therapeutic targets for metabolic dysfunction-associated steatotic liver disease (MASLD). Through scaffold-conservative optimization of an imidazo[2,1-<i>b</i>][1,3,4]thiadiazole core, we identified HD202A as a highly potent MNK1/2 inhibitor (IC₅₀ = 6.1/8.1 nM) with favorable kinome selectivity within the tested kinase panel, oral bioavailability (F = 42.1%), and favorable pharmacokinetic properties. In a high-fat-diet induced MASLD mice, HD202A markedly reduced body-weight gain, hepatic triglyceride accumulation, and serum lipids while improving glucose tolerance, insulin sensitivity, and inflammatory profiles. Mechanistically, HD202A suppressed MNK-eIF4E signaling, downregulated perilipin 2 and stearoyl-coenzyme A desaturase 1, upregulated adipose triglyceride lipase and peroxisome proliferator-activated receptor gamma coactivator 1α, and enhanced mitochondrial fatty-acid oxidation and redox homeostasis. These findings validate MNK inhibition as a viable strategy for MASLD and establish HD202A as a promising lead compound for further development.