Stereo- and regiodefined DNA-encoded chemical libraries enable efficient tumour-targeting applications

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Drug Discovery

Background:

• DNA-encoded libraries (DELs) are powerful tools for identifying small-molecule ligands.
• Understanding the influence of chemical structure, specifically stereochemistry and regiochemistry, is crucial for optimizing ligand discovery.
• The 2-azido-3-iodophenylpropionic acid scaffold offers a versatile platform for generating diverse chemical libraries.

Purpose of the Study:

• To investigate the impact of stereo- and regiochemistry on ligand discovery using a DNA-encoded library.
• To identify novel small-molecule ligands for pharmaceutically relevant protein targets.
• To explore the therapeutic potential of discovered ligands in areas like enzyme inhibition and cancer therapy.

Main Methods:

• Synthesis of a large DNA-encoded library (670,752 derivatives) based on 2-azido-3-iodophenylpropionic acids.
• Selection of the library against multiple protein targets.
• Analysis of selection fingerprints to determine regioisomer enrichment.
• Experimental verification of ligand affinity through binding assays.

Main Results:

• The DNA-encoded library successfully yielded specific ligands for multiple protein targets.
• Selection fingerprints revealed distinct preferences for ortho-, meta-, or para-regioisomers depending on the protein target.
• Experimental validation confirmed the affinity of selected ligands, demonstrating the importance of regiochemistry.
• Discovered ligands included novel selective enzyme inhibitors and binders to tumor-associated antigens.

Conclusions:

• Stereo- and regiochemistry significantly impact DNA-encoded library-based ligand discovery.
• The developed library and selection strategy are effective for identifying potent and selective ligands.
• The identified ligands show promise for therapeutic applications, including targeted cancer therapy and conditional chimeric antigen receptor T-cell activation.