Jeremy W. Mason; Liam Hudson; Matthias V. Westphal; Antonin Tutter; Gregory Michaud; Wei Shu; Xiaolei Ma; Connor W. Coley; Paul A Clemons; Simone Bonazzi; Frédéric Berst; Frédéric J. Zécri; Karin Briner; Stuart L. Schreiber
bioRxiv, 2022
https://doi.org/10.1101/2022.10.13.512184

Abstract

Molecular glues and bifunctional compounds that induce protein-protein associations provide a powerful and general mechanism to modulate cell circuitry. We sought to develop a platform for the direct discovery of compounds able to induce association of any two pre-selected proteins, using the first bromodomain of BRD4 and the VHL-elongin C-elongin B (VCB) complex as a test system. Leveraging the screening power of DNA-encoded libraries (DELs), we synthesized ~one million DNA-encoded compounds that possess a VHL-targeting fragment, a variety of connectors, and a diversity element generated by split-and-pool combinatorial chemistry. By screening our DEL against BRD4 in the presence and absence of VCB, we could identify VHL-bound molecules that simultaneously bind BRD4. For highly barcode-enriched library members, ternary complex formation leading to BRD4 degradation was confirmed in cells. Furthermore, a ternary complex crystal structure was obtained for the most enriched library member. Our work provides a foundation for adapting DEL screening to the discovery of proximity-inducing small molecules.