![]() The most effective molecule in our screening was MS-275 (also known as entinostat), a Class 1 HDAC inhibitor that inhibits HDAC1 and HDAC3 with comparable potency ( Lauffer et al., 2013). Our data showed that Suberoylanilide Hydroxamic Acid (SAHA), Trichostatin A, AR-42, and MS-275 enhanced GLP-1R agonism of liraglutide in cultured pancreatic beta cells. These compounds are not direct GLP-1R agonists as assessed by their independent inability to promote cAMP generation acutely in BRIN-BD11 pancreatic beta cells ( Figure 1-figure supplement 1). Interestingly, each of these compounds is an HDAC inhibitor possessing either a hydroxamate or an orthoanilide group. Four compounds enhanced the GLP-1R-mediated cAMP generation ( Figure 1A, Supplementary file 1-Table 1). The screening paradigm involved incubation of BRIN–BD11 pancreatic beta cells with each small molecule for 18h before being stimulated with liraglutide for the cAMP response. ![]() We screened an unbiased compound library comprising of 150 small molecules to search for the enhancement of the activity of GLP-1R agonist, liraglutide. The data, taken together thus provides a new dimension to the treatment of T2D and obesity. Our findings show that MS-275 enhances the expression of the genes involved in the GLP-1R signaling cascade improving fasting glycemia upon a short-term treatment and a chronic combined therapy reduces obesity in the DIO rodent model. From a relatively smaller compound library, four Class 1 HDAC inhibitors were confirmed to enhance GLP-1R-mediated signaling, the most prominent among them being the Class 1 HDAC-inhibitor named Entinostat (MS-275) ( Suzuki et al., 1999 Saito et al., 1999). We report herein the identification of a small molecule inhibitor of Class 1 histone deacetylases (HDACs) that significantly enhances the GLP-1R signaling. If so, the metabolic and body weight benefits of GLP-1 therapy would be sizably enhanced. These results led to our hypothesis to assess whether the increase in the expression of the auxiliary proteins that supports GPCR-mediated sustained cAMP generation could enhance GLP-1R function. Previous observations from our laboratory have shown that prolonged association of the Gα s subunit with the activated and internalized GLP-1R at Rab5 endosomes sustains cAMP generation to support GSIS in pancreatic beta cells ( Girada et al., 2017). More recent reports, however, demonstrate sustained cAMP generation for several GPCRs following internalization and the formation of a multi-protein complex at endosomes where activated receptor-ligand complex, the Gα s subunit of the heterotrimeric G-protein and beta arrestin-1 contribute as key components ( Thomsen et al., 2016). The canonical pathway of GPCR activation postulates increases in the second messenger cAMP following the receptor activation that rapidly attenuates with the receptor internalization and desensitization. The activation of the receptor propels a cellular signaling cascade that eventually potentiates glucose-stimulated insulin secretion (GSIS) ( Drucker, 2006). In each instance, the receptor stabilizes in an active conformation suitable for the association with heterotrimeric G-protein subunit Gα s and subsequent activation of the adenylate cyclase. Incretin receptors can be activated by orthosteric peptide-based agonists ( Drucker et al., 2010), dual agonists ( Finan et al., 2013), and small-molecule allosteric modulators ( Knudsen et al., 2007 Bueno et al., 2016). The unmet medical need warrants additional complementary mechanisms to incretin action ( Tschöp and DiMarchi, 2017) or a novel approach to supplement incretin pharmacology. ![]() Unfortunately, not all patients achieve normal glucose control, and even fewer show reversal of obesity ( Amori et al., 2007). Incretin-based therapy and specifically glucagon-like peptide 1 receptor (GLP-1R) agonists provide sizable glycemic benefit and modest improvement in the body weight ( Astrup et al., 2009). Type 2 diabetes (T2D) and obesity have reached global epidemic levels and required a therapeutic intervention to reduce the burden of the disease.
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