DI-1859

DI-1859 is a selective inhibitor of Cullin 3 (Cul3) neddylation, a post-translational modification essential for the activation of Cullin-RING E3 ligases (CRLs). By specifically targeting Cul3, DI-1859 exerts dual therapeutic effects for the treatment of type 2 diabetes (T2D), acting as both an insulin sensitizer and an insulinotropic agent. Mechanistically, Cul3 inhibition prevents the degradation of insulin receptor substrates (IRS), thereby prolonging insulin signaling, reducing hepatic glucose production, and enhancing glucose uptake in skeletal muscle. Additionally, DI-1859 promotes glucose-stimulated insulin secretion (GSIS) in pancreatic beta cells and human islets. In preclinical models of obesity, DI-1859 has demonstrated the ability to lower blood glucose levels and improve whole-body insulin sensitivity.