Narrative cv coming soon 

Abstract: Type 2 diabetes (T2D) is an increasingly severe global health and economic burden, affecting approximately half a billion adults in 2021 and projected to still strongly rise. A promising therapeutic target for T2D is the Carbohydrate Response Element Binding Protein (ChREBP), a glucose-responsive transcription factor with two major splice isoforms (α and β). In chronic hyperglycaemia and glucolipotoxicity, ChREBPα-mediated ChREBPβ expression surges, leading to dedifferentiation and death of insulin-secreting β-cells. Binding of the 14-3-3 protein to ChREBPα results in cytoplasmic retention and suppression of its transcriptional activity. Thus, small molecule-mediated stabilization of the ChREBPα/14-3-3 protein-protein interaction (PPI) may be of therapeutic value. We show that structure-based optimization of a ‘molecular glue’ compound led to potent ChREBPα/14-3-3 PPI stabilizers with cellular activity. In primary human β-cells, the most active compound retains ChREBPα in the cytoplasm, thereby protecting β-cells from glucolipotoxicity while maintaining β-cell identity. These findings provide the basis for the development of a unique class of T2D therapeutics and illustrate an innovative “molecular glue” approach to modulate transcription factors that are notoriously difficult to target with small molecules.