Fragment-Based Stabilizers of Protein-Protein Interactions through Imine-Based Tethering

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Drug Discovery

Background:

• Small-molecule stabilization of protein-protein interactions (PPIs) is a key strategy in drug discovery.
• Identifying effective chemical starting points for PPI stabilization remains a significant challenge.
• A "bottom-up" approach for designing PPI stabilizers is needed.

Purpose of the Study:

• To introduce a novel concept for identifying initial chemical matter for PPI stabilization.
• To utilize imine-forming fragments for targeted covalent inhibition and structure-activity relationship analysis.
• To discover novel fragments that stabilize the 14-3-3/p65 complex.

Main Methods:

• Employed imine-forming fragments for site-directed fragment targeting.
• Utilized protein crystallography for fragment identification and optimization.
• Investigated fragments binding to the p65-subunit-derived peptide of NF-κB and 14-3-3 protein.

Main Results:

• Identified novel fragments that specifically bind to a lysine at the PPI interface.
• Demonstrated that fragments contacting the p65-derived peptide efficiently stabilize the 14-3-3/p65 complex.
• Established a new strategy for fragment-based PPI stabilization.

Conclusions:

• Imine-forming fragments provide a viable strategy for identifying PPI stabilizers.
• This method offers novel starting points for developing molecular glues.
• The transient nature of imine bonds facilitates efficient SAR analysis.