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

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Area of Science:

  • Medicinal Chemistry
  • Chemical Biology
  • Drug Discovery

Background:

  • Molecular glues are small molecules that modulate protein-protein interactions (PPIs) by binding to protein interfaces.
  • Targeting
  • undruggable
  • proteins remains a key challenge in drug discovery.
  • Developing systematic methods for identifying novel molecular glues is crucial.

Purpose of the Study:

  • To present a novel scaffold hopping approach for discovering and optimizing molecular glues.
  • To design and synthesize new molecular glue analogs targeting the 14-3-3/estrogen receptor alpha (ERα) complex.
  • To demonstrate the utility of multi-component reaction (MCR) chemistry in generating diverse molecular glue scaffolds.

Main Methods:

  • Scaffold hopping based on previously identified 14-3-3/ERα molecular glues.
  • Computational design and synthesis utilizing the Groebke-Blackburn-Bienaymé MCR.
  • Structure-activity relationship (SAR) studies using biophysical assays (mass spectrometry, TR-FRET, SPR).
  • Structure-guided optimization informed by crystal structures of ternary complexes.
  • Cellular validation using NanoBRET assays with full-length proteins.

Main Results:

  • Novel, drug-like molecular glue analogs were generated using MCR chemistry.
  • Multiple crystal structures elucidated the binding mode of ternary complexes.
  • Potent analogs demonstrated cellular stabilization of the 14-3-3/ERα complex.
  • The scaffold hopping approach enabled rapid derivatization and optimization.

Conclusions:

  • The combination of MCR chemistry and scaffold hopping is effective for developing novel molecular glue scaffolds.
  • This strategy facilitates the optimization of molecular glues for challenging PPI targets.
  • The developed molecular glues show potential for modulating the 14-3-3/ERα interaction in cellular contexts.