The inhibitor VB-87531 synergizes with tirzepatide and semaglutide for greater weight loss in DIO mice.

Excessive caloric intake, particularly dietary triglycerides contributes to the development of obesity. Monoacylglycerol acyltransferase 2 (hMOGAT2/mMgat2) plays a crucial role in their resynthesis for their transport to the liver. The human MOGAT2 inhibitor BMS-963272 has been demonstrated to induce weight loss in healthy obese individuals, thereby positioning hMOGAT2 as a promising target for weight management interventions. We have identified VB-87531 as a highly potent (IC = 17.4 nM) small molecule inhibitor of hMOGAT2 activity and demonstrate that administration of VB-87531 to obese mice fed a high-fat diet results in weight loss and reduced food intake. VB-87531-treated mice exhibit lower blood cholesterol and glucose levels relative to untreated controls, with no observed liver toxicity. Furthermore, VB-87531 in combination with either the GLP-1/GIP dual receptor agonist, tirzepatide, or the GLP-1 receptor agonist, semaglutide, resulted in enhanced weight loss and reduced food intake compared to VB-87531 monotherapy. Combination therapy also significantly lowered insulin and leptin levels while increasing FGF21 and PYY. When combined with tirzepatide, VB-87531 exhibited dose-dependent modulation of weight loss and food intake. These findings indicate that not only does VB-87531 have potential as a standalone therapy, but that it also holds promise in combination with GLP-1 receptor and GLP-1/GIP dual receptor agonists to achieve further weight loss and appetite suppression.