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

TY - JOUR

T1 - Molecular glues of the regulatory ChREBP/14-3-3 complex protect beta cells from glucolipotoxicity

AU - Katz, Liora S.

AU - Visser, Emira J.

AU - Plitzko, Kathrin F.

AU - Pennings, Marloes A. M.

AU - Cossar, Peter J.

AU - Tse, Isabelle L.

AU - Kaiser, Markus

AU - Brunsveld, Luc

AU - Ottmann, Christian

AU - Scott, Donald K.

N1 - Publisher Copyright: © The Author(s) 2025.

PY - 2025/3/2

Y1 - 2025/3/2

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85219632455

U2 - 10.1038/s41467-025-57241-7

DO - 10.1038/s41467-025-57241-7

M3 - Article

C2 - 40025013

AN - SCOPUS:85219632455

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

M1 - 2110

ER -