Katz Liora S, Visser Emira J, Plitzko Kathrin F, Pennings Marloes A M, Cossar Peter J, Tse Isabelle L, Kaiser Markus, Brunsveld Luc, Ottmann Christian, Scott Donald K
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.
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.
bioRxiv. 2024 Nov 17:2024.02.16.580675. doi: 10.1101/2024.02.16.580675.
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.
碳水化合物反应元件结合蛋白（ChREBP）是一种葡萄糖反应性转录因子（TF），有两种主要的剪接异构体（α和β）。在慢性高血糖和糖脂毒性状态下，ChREBPα介导的ChREBPβ表达激增，导致分泌胰岛素的β细胞去分化和死亡。14-3-3与ChREBPα结合会导致其滞留于细胞质并抑制转录活性。因此，小分子介导的这种蛋白质-蛋白质相互作用（PPI）的稳定化可能具有治疗价值。在此，我们表明基于结构对一种“分子胶”化合物进行优化可产生具有细胞活性的强效ChREBPα/14-3-3 PPI稳定剂。在原代人β细胞中，活性最强的化合物可使ChREBPα保留在细胞质中，并有效保护β细胞免受糖脂毒性影响，同时维持β细胞特性。因此，本研究不仅可为开发一类独特的用于治疗2型糖尿病的化合物提供依据，还展示了一种替代的“分子胶”方法，用于实现对难以靶向的转录因子进行小分子调控。
