Discovery of Potent and Selective Imidazo[2,1‑b][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-b][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.