Higher order iminodiacetic acid libraries for probing protein-protein interactions

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Drug Discovery

Background:

• Protein-protein interactions (PPIs) are crucial in biological processes.
• Developing small molecules to modulate PPIs is a significant challenge in drug discovery.

Purpose of the Study:

• To synthesize diverse libraries of iminodiacetic acid diamide dimers, trimers, and tetramers.
• To establish a platform for identifying novel modulators of PPIs.
• To explore structure-activity relationships for lead compounds.

Main Methods:

• Multistep convergent solution-phase synthesis was employed to create compound libraries.
• Libraries were assembled into small mixtures (8-10 compounds) for efficient screening.
• Deconvolution of active mixtures by resynthesis of individual compounds was performed.

Main Results:

• Successfully synthesized large libraries of iminodiacetic acid diamide dimers (2040), trimers (560), and tetramers (1596).
• Identified 320 individual compounds through mixture deconvolution.
• Characterized structure-activity relationships for a receptor binding antagonist, synthesizing 200 additional compounds.
• Prepared 70 linked dimers for potential elaboration to receptor dimerization agonists.

Conclusions:

• The developed synthetic strategy enables the creation of extensive compound libraries for PPI research.
• The identified antagonist serves as a promising starting point for developing receptor dimerization agonists.
• This work provides a robust framework for the discovery of novel PPI modulators.