Discovery of 14-3-3 PPI Stabilizers by Extension of an Amidine-Substituted Thiophene Fragment

Qi Wu, Federica Centorrino, Xavier Guillory, Madita Wolter, Christian Ottmann (Lead / Corresponding author), Peter J. Cossar (Lead / Corresponding author), Luc Brunsveld (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)
29 Downloads (Pure)

Abstract

Protein-protein interaction (PPI) modulation is a promising approach in drug discovery with the potential to expand the ‘druggable’ proteome and develop new therapeutic strategies. While there have been significant advancements in methodologies for developing PPI inhibitors, there is a relative scarcity of literature describing the ‘bottom-up’ development of PPI stabilizers (Molecular Glues). The hub protein 14-3-3 and its interactome provide an excellent platform for exploring conceptual approaches to PPI modulation, including evolution of chemical matter for Molecular Glues. In this study, we employed a fragment extension strategy to discover stabilizers for the complex of 14-3-3 protein and an Estrogen Receptor alpha-derived peptide (ERα). A focused library of analogues derived from an amidine-substituted thiophene fragment enhanced the affinity of the 14-3-3/ERα complex up to 6.2-fold. Structure-activity relationship (SAR) analysis underscored the importance of the newly added, aromatic side chain with a certain degree of rigidity. X-ray structural analysis revealed a unique intermolecular π–π stacking binding mode of the most active analogues, resulting in the simultaneous binding of two molecules to the PPI binding pocket. Notably, analogue 11 displayed selective stabilization of the 14-3-3/ERα complex.

Original languageEnglish
Article numbere202300636
Number of pages9
JournalChemBioChem
Volume25
Issue number1
Early online date30 Oct 2023
DOIs
Publication statusPublished - 2 Jan 2024

Keywords

  • 14-3-3
  • Erα
  • Fragment
  • Molecular Glue
  • PPI Stabilizer

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

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