Novel GLP-1RA-like effects of Bafetinib: a preliminary study integrated in vitro screening and in vivo validation

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are first-line treatments for type 2 diabetes mellitus and obesity. Nevertheless, their clinical application is constrained by the adimistration route of subcutaneous injection and the safety concerns including gastrointestinal side effects.Aiming to screen novel compounds with potent GLP-1RA-like activityand good safety, and can be given orally, we performed structure-based virtual screening of a library, subsequent surface plasmon resonance and molecular docking analyses in this study. The results showed that Bafetinib stood our from the library with high high binding affinity to GLP-1R and great thermal stability. Moreover, results of the in vitro study, demonstrated that Bafetinib could upregulated the expression of GLP-1R in cultured Min6 and HT22 cells, together with increased levels of intracellular cAMP, PKA, and phosphorylated CREB·In C57BL/6 mice, consecutive 7 days' administration of Bafetinib resulted in a loss of body weight and postprandial blood glucose, but not fasting glucose, similar to the effect of Exendin-4, which is a reagent of GLP-1RA. Histopathological assessment further indicated no significant toxicity in major organs. Overall, these results clarify that Bafetinib can bind and activate GLP-1R, and exert GLP-1RA-like activity orally and safetly in mice.