biostudies-literatureMason JWU.S. Department of Health & Human Services | NIH | National Institute of General Medical SciencesNIGMS NIH HHS170-179https://www.ebi.ac.uk/biostudies/studies/S-EPMC10917151biostudies-literatureUnknown20(2)Small molecules that induce protein-protein associations represent powerful tools to modulate cell circuitry. We sought to develop a platform for the direct discovery of compounds able to induce association of any two preselected proteins, using the E3 ligase von Hippel-Lindau (VHL) and bromodomains as test systems. Leveraging the screening power of DNA-encoded libraries (DELs), we synthesized ~1 million DNA-encoded compounds that possess a VHL-targeting ligand, a variety of connectors and a diversity element generated by split-and-pool combinatorial chemistry. By screening our DEL against bromodomains in the presence and absence of VHL, we could identify VHL-bound molecules that simultaneously bind bromodomains. For highly barcode-enriched library members, ternary complex formation leading to bromodomain degradation was confirmed in cells. Furthermore, a ternary complex crystal structure was obtained for our most enriched library member with BRD4^BD1 and a VHL complex. Our work provides a foundation for adapting DEL screening to the discovery of proximity-inducing small molecules.Nature chemical biologyDNA-encoded library-enabled discovery of proximity-inducing small molecules.PMC10917151R35GM127045R35 GM127045Chow YTWestphal MVBerst FMa XMichaud GLiu SClemons PAMason JWTutter AZecri FJBriner KColey CWSchreiber SLShu WBonazzi SHudson LTan ZYfalseDNA-encoded library-enabled discovery of proximity-inducing small molecules.Small molecules that induce protein-protein associations represent powerful tools to modulate cell circuitry. We sought to develop a platform for the direct discovery of compounds able to induce association of any two preselected proteins, using the E3 ligase von Hippel-Lindau (VHL) and bromodomains as test systems. Leveraging the screening power of DNA-encoded libraries (DELs), we synthesized ~1 million DNA-encoded compounds that possess a VHL-targeting ligand, a variety of connectors and a diversity element generated by split-and-pool combinatorial chemistry. By screening our DEL against bromodomains in the presence and absence of VHL, we could identify VHL-bound molecules that simultaneously bind bromodomains. For highly barcode-enriched library members, ternary complex formation leading to bromodomain degradation was confirmed in cells. Furthermore, a ternary complex crystal structure was obtained for our most enriched library member with BRD4^BD1 and a VHL complex. Our work provides a foundation for adapting DEL screening to the discovery of proximity-inducing small molecules.2024-01-01T00:00:00Z2024 Feb2026-06-01T05:09:30.933Z2025-04-05T10:19:49.48ZS-EPMC109171513791954910.1038/s41589-023-01458-4