Scaffold-hopping for molecular glues targeting the 14-3-3/ERα complex

  • Nat Commun. 2025 Jul 14;16(1):6467. doi: 10.1038/s41467-025-61176-4.
Markella Konstantinidou  1 ,  Marios Zingiridis  2 ,  Marloes A M Pennings  3 ,  Michael Fragkiadakis  2 ,  Johanna M Virta  4 ,  Jezrael L Revalde  4 ,  Emira J Visser  3 ,  Christian Ottmann  3 ,  Luc Brunsveld  3 ,  Constantinos G Neochoritis  5 ,  Michelle R Arkin  6
Affiliations
  • 1. Department of Pharmaceutical Chemistry and Small Molecule Discovery Centre (SMDC) University of California San Francisco (UCSF), San Francisco, CA, USA. [email protected].
  • 2. Department of Chemistry University of Crete Voutes, Heraklion, Greece.
  • 3. Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS) Eindhoven University of Technology, 5600 MB, Eindhoven, The Netherlands.
  • 4. Department of Pharmaceutical Chemistry and Small Molecule Discovery Centre (SMDC) University of California San Francisco (UCSF), San Francisco, CA, USA.
  • 5. Department of Chemistry University of Crete Voutes, Heraklion, Greece. [email protected].
  • 6. Department of Pharmaceutical Chemistry and Small Molecule Discovery Centre (SMDC) University of California San Francisco (UCSF), San Francisco, CA, USA. [email protected].
PMID: 40659654 DOI: 10.1038/s41467-025-61176-4
Abstract

Molecular Glues, small molecules that bind cooperatively at a protein-protein interface, have emerged as powerful modalities for the modulation of protein-protein interactions (PPIs) and "undruggable" targets. The systematic identification of new chemical matter with a molecular glue mechanism of action remains a significant challenge in drug discovery. Here, we present a scaffold hopping approach, using as a starting point our previously developed Molecular Glues for the native 14-3-3/Estrogen receptor alpha (ERα) complex. The novel, computationally designed scaffold is based on the Groebke-Blackburn-Bienaymé multi-component reaction (MCR), leading to drug-like analogs with multiple points of variation, thus enabling the rapid derivatization and optimization of the scaffold. Structure-activity relationships (SAR) are developed using orthogonal biophysical assays, such as intact mass spectrometry, TR-FRET and SPR. Rational structure-guided optimization is facilitated by multiple crystal structures of ternary complexes with the glues, 14-3-3 and phospho-peptides mimicking the highly disordered C-terminus of ERα. Cellular stabilization of 14-3-3/ERα for the most potent analogs is confirmed using a NanoBRET assay with full-length proteins in live cells. Our approach highlights the potential of MCR chemistry, combined with scaffold hopping, to drive the development and optimization of unprecedented molecular glue scaffolds.

Products