Molecular glues of the regulatory ChREBP/14-3-3 complex protect beta cells from glucolipotoxicity.

Autor:	Katz LS; Diabetes, Obesity and Metabolism Institute and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1152, New York, 10029, USA., Visser EJ; Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands., Plitzko KF; Chemical Biology, Center of Medical Biotechnology, Faculty of Biology, University of Duisburg-Essen, Duisburg, Germany., Pennings M; Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands., Cossar PJ; Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands., Tse IL; Diabetes, Obesity and Metabolism Institute and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1152, New York, 10029, USA., Kaiser M; Chemical Biology, Center of Medical Biotechnology, Faculty of Biology, University of Duisburg-Essen, Duisburg, Germany., Brunsveld L; Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands., Scott DK; Diabetes, Obesity and Metabolism Institute and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1152, New York, 10029, USA., Ottmann C; Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Feb 17. Date of Electronic Publication: 2024 Feb 17.
DOI:	10.1101/2024.02.16.580675
Abstrakt:	The Carbohydrate Response Element Binding Protein (ChREBP) is a glucose-responsive transcription factor (TF) that is characterized by two major splice isoforms (α and β). In acute hyperglycemia, both ChREBP isoforms regulate adaptive β-expansion; however, during chronic hyperglycemia and glucolipotoxicity, ChREBPβ expression surges, leading to β-cell dedifferentiation and death. 14-3-3 binding to ChREBPα results in its cytoplasmic retention and concomitant suppression of transcriptional activity, suggesting that small molecule-mediated stabilization of this protein-protein interaction (PPI) via molecular glues may represent an attractive entry for the treatment of metabolic disease. Here, we show that structure-based optimizations of a molecular glue tool compound led not only to more potent ChREBPα/14-3-3 PPI stabilizers but also for the first time cellular active compounds. In primary human β-cells, the most active compound stabilized the ChREBPα/14-3-3 interaction and thus induced cytoplasmic retention of ChREBPα, resulting in highly efficient β-cell protection 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 targetable TFs. Competing Interests: The authors declare the following competing financial interest(s): L.B. and C.O. are founders of Ambagon Therapeutics. L.B. is a member of Ambagon’s scientific advisory board, C.O. is employee of Ambagon.
Databáze:	MEDLINE
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