DNA-encoded library-enabled discovery of proximity-inducing small molecules.

Area of Science:

• Chemical Biology
• Molecular Biology
• Drug Discovery

Background:

• Small molecules modulating protein-protein interactions are key for controlling cellular processes.
• Developing methods to discover molecules that induce specific protein associations is crucial for chemical biology.

Purpose of the Study:

• To create a versatile platform for discovering small molecules that induce the association of any two target proteins.
• To utilize DNA-encoded libraries (DELs) for efficient screening of proximity-inducing compounds.

Main Methods:

• Synthesized a DNA-encoded library of approximately 1 million compounds featuring a von Hippel-Lindau (VHL) E3 ligase-targeting ligand.
• Screened the DEL against bromodomains in the presence and absence of VHL to identify molecules forming ternary complexes.
• Confirmed ternary complex formation and subsequent bromodomain degradation in cells for enriched compounds.

Main Results:

• Identified VHL-recruiting molecules that simultaneously bind bromodomains.
• Demonstrated targeted protein degradation of bromodomains mediated by the identified small molecules.
• Obtained a ternary complex crystal structure of a VHL-BRD4 complex with a discovered small molecule.

Conclusions:

• Established a DNA-encoded library screening strategy for discovering proximity-inducing small molecules.
• The developed platform provides a foundation for targeted protein degradation and modulation of protein-protein interactions.
• This approach enables the discovery of novel chemical tools for chemical biology and drug discovery.