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

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.