2025-03-04 マウントサイナイ医療システム (MSHS)
<関連情報>
- https://www.mountsinai.org/about/newsroom/2025/mount-sinai-researchers-identify-molecular-glues-that-protect-insulin-producing-cells-from-damage-related-to-diabetes
- https://www.nature.com/articles/s41467-025-57241-7
制御ChREBP/14-3-3複合体の分子接着剤がβ細胞を糖脂質毒性から保護する Molecular glues of the regulatory ChREBP/14-3-3 complex protect beta cells from glucolipotoxicity
Liora S. Katz,Emira J. Visser,Kathrin F. Plitzko,Marloes A. M. Pennings,Peter J. Cossar,Isabelle L. Tse,Markus Kaiser,Luc Brunsveld,Christian Ottmann & Donald K. Scott
Nature Communications Published:02 March 2025
DOI:https://doi.org/10.1038/s41467-025-57241-7
Abstract
The Carbohydrate Response Element Binding Protein (ChREBP) is a glucose-responsive transcription factor (TF) with two major splice isoforms (α and β). In chronic hyperglycemia and glucolipotoxicity, ChREBPα-mediated ChREBPβ expression surges, leading to insulin-secreting β-cell dedifferentiation and death. 14-3-3 binding to ChREBPα results in cytoplasmic retention and suppression of transcriptional activity. Thus, small molecule-mediated stabilization of this protein-protein interaction (PPI) may be of therapeutic value. Here, we show that structure-based optimizations 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 retained ChREBPα in the cytoplasm, and efficiently protected β-cells from glucolipotoxicity while maintaining β-cell identity. This study may thus not only provide the basis for the development of a unique class of compounds for the treatment of Type 2 Diabetes but also showcases an alternative ‘molecular glue’ approach for achieving small molecule control of notoriously difficult to target TFs.
