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bioRxiv · 10.1101/2025.11.09.687522

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

Wang, L.·Tao, X.·He, M.·Lu, Y.·Wang, Y.·Zhu, J.
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Abstract

Hydroxysteroid 11-beta dehydrogenase 1 (11{beta}-HSD1) plays a critical role in metabolic homeostasis by catalyzing the intracellular conversion of cortisone to cortisol. Dysregulated 11{beta}-HSD1 activity is closely associated with metabolic disorders such as type 2 diabetes mellitus, obesity, and glucocorticoid-related inflammation. While small-molecule inhibitors of 11{beta}-HSD1 have shown promise, they primarily suppress enzymatic activity without modulating protein abundance. Here, we report the development of the 11{beta}-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 11{beta}-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 energetics compared to less active analogs. Collectively, this study introduces a novel chemical modality for 11{beta}-HSD1 modulation and lays the groundwork for future therapeutic development targeting metabolic disease via selective protein degradation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=101 SRC="FIGDIR/small/687522v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@60aa3borg.highwire.dtl.DTLVardef@484120org.highwire.dtl.DTLVardef@1abca2eorg.highwire.dtl.DTLVardef@166b1a3_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Wang, L., Tao, X., He, M., Lu, Y., Wang, Y., Zhu, J.. 2025-11-10. Design, synthesis, and pharmacological evaluation of novel PROTAC degraders targeting 11β-HSD1 for metabolic disease intervention. https://doi.org/10.1101/2025.11.09.687522

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