ArticlebioRxiv : the preprint server for biology2024
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
Open access · greenAbstract readPreprint
In one paragraphArticle in bioRxiv : the preprint server for biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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5 · Who and what moneyAuthors and funding
10 authors at 3 institutions in 3 countries.
Liora S KatzDiabetes, 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.ORCID 0000-0002-3097-0767 Emira J VisserLaboratory 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.
Kathrin F PlitzkoChemical Biology, Center of Medical Biotechnology, Faculty of Biology, University of Duisburg-Essen, 45141 Essen, Germany.
Marloes A M PenningsLaboratory 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.
Peter J CossarLaboratory 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.
Isabelle L TseDiabetes, 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.
Markus KaiserChemical Biology, Center of Medical Biotechnology, Faculty of Biology, University of Duisburg-Essen, 45141 Essen, Germany.ORCID 0000-0002-6540-8520 Luc BrunsveldLaboratory 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.ORCID 0000-0001-5675-511X Christian OttmannLaboratory 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.ORCID 0000-0001-7315-0315 Donald K ScottDiabetes, 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.
Eindhoven University of Technology · NLChild Health and Development Institute · USUniversity of Duisburg-Essen · DE
Funding
Translational Research CoreP30DK020541 · NIDDK · ALBERT EINSTEIN COLLEGE OF MEDICINE, INC · PI STREAMSON C CHUA · 2015 to 2026
$27.7MAlleviation of Glucotoxicity in Pancreatic Beta CellsR01DK130300 · NIDDK · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI SCOTT, DONALD K. · 2021 to 2024
$2.0MNIDDK NIH HHS P30 DK020541NIDDK NIH HHS R01 DK130300
6 · The paper itselfAbstract
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.
Identifiers
PMID38405965
PMCPMC10888794
OpenAlexW4391913285
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