ArticleNature communications2025
Molecular glues of the regulatory ChREBP/14-3-3 complex protect beta cells from glucolipotoxicity.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
14 citing papers in PubMed.
- Monovalent Nondegrading Molecular Glues: An Updated Overview of Emerging Mechanisms and Therapeutic Development.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Phosphoinositides and inositol phosphates as molecular glues.FEBS letters · 2026Review
- Sugar Shockwaves: How the Fructose-Glucose-ChREBP Pathway Hijacks Liver Metabolism.Life (Basel, Switzerland) · 2026Review
- Induced ubiquitination of the partially disordered estrogen receptor alpha via a 14-3-3 directed molecular glue-PROTAC.Nature communications · 2026Article
- ChREBP Is Dispensable for Myofiber Type Switch but Promotes Skeletal Muscle Regeneration.Nutrients · 2026Article
- Restoring the 14-3-3/CRAF regulatory interaction in Noonan syndrome using molecular glues.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- EIF4A3-induced circUBAC2 promotes lung cancer progression via regulation of the Hippo signaling pathway.Cellular & molecular biology letters · 2026Article
- From Serendipity to Strategy: Rationalizing Molecular Glue Discovery and Proximity-Induced Pharmacology through Chemical Biology.Journal of the American Chemical Society · 2026Review
- Modulation of the 14-3-3σ/C-RAF "Auto"inhibited Complex by Molecular Glues.Journal of the American Chemical Society · 2026Article
- Macrocyclic Molecular Glues for the 14-3-3/ChREBP Interaction: Affinity and Cooperativity in an Inverse Relationship.Angewandte Chemie (International ed. in English) · 2026Article
- A Novel Paradigm for Targeting Challenging Targets: Advancing Technologies and Future Directions of Molecular Glue Degraders.Molecules (Basel, Switzerland) · 2026Review
- Role of ChREBP-PPARα-FGF21 Axis in Metabolic Dysfunction of MASLD.International journal of molecular sciences · 2025Article
- Stabilization of Native Protein-Protein Interactions with Molecular Glues: A 14-3-3 Case Study.Accounts of chemical research · 2025Article
- 14-3-3 Protein-Protein Interactions: From Mechanistic Understanding to Their Small-Molecule Stabilization.Chembiochem : a European journal of chemical biology · 2024Review
Corrections and comments
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Authors and funding
10 authors.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.