Design, synthesis, and pharmacological evaluation of novel PROTAC degraders targeting 11β-HSD1 for metabolic disease...

Hydroxysteroid 11-beta dehydrogenase 1 (11β-HSD1) plays a critical role in metabolic homeostasis by catalyzing the intracellular conversion of cortisone to cortisol. Dysregulated 11β-HSD1 activity is closely associated with metabolic disorders such as type 2 diabetes mellitus, obesity, and glucocorticoid-related inflammation. While small-molecule inhibitors of 11β-HSD1 have shown promise, they primarily suppress enzymatic activity without modulating protein abundance. Here, we report the development of the 11β-HSD1-targeting PROTAC degraders. A series of bifunctional molecules were synthesized based on CRBN- and VHL-recruiting ligands, with AZD8329-derived warheads linked via polyethylene glycol chains. Cellular assays demonstrated efficient, ubiquitin-proteasome-dependent degradation of 11β-HSD1, with H-3-V identified as the most potent degrader. In vivo, H-3-V treatment improved glucose tolerance and enhanced glucose-stimulated insulin secretion in a high-fat diet-induced T2DM mouse model. Molecular dynamics simulations revealed that the H-3-V ternary complex exhibited superior binding energy compared to less active analogs. Collectively, this study introduces a novel chemical modality for 11β-HSD1 modulation and lays the groundwork for future therapeutic development targeting metabolic diseases via protein degradation.