{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Mason JW"],"funding":["U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences","NIGMS NIH HHS"],"pagination":["170-179"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10917151"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["20(2)"],"pubmed_abstract":["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<sup>BD1</sup> and a VHL complex. Our work provides a foundation for adapting DEL screening to the discovery of proximity-inducing small molecules."],"journal":["Nature chemical biology"],"pubmed_title":["DNA-encoded library-enabled discovery of proximity-inducing small molecules."],"pmcid":["PMC10917151"],"funding_grant_id":["R35GM127045","R35 GM127045"],"pubmed_authors":["Chow YT","Westphal MV","Berst F","Ma X","Michaud G","Liu S","Clemons PA","Mason JW","Tutter A","Zecri FJ","Briner K","Coley CW","Schreiber SL","Shu W","Bonazzi S","Hudson L","Tan ZY"],"additional_accession":[]},"is_claimable":false,"name":"DNA-encoded library-enabled discovery of proximity-inducing small molecules.","description":"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<sup>BD1</sup> and a VHL complex. Our work provides a foundation for adapting DEL screening to the discovery of proximity-inducing small molecules.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Feb","modification":"2026-06-01T05:09:30.933Z","creation":"2025-04-05T10:19:49.48Z"},"accession":"S-EPMC10917151","cross_references":{"pubmed":["37919549"],"doi":["10.1038/s41589-023-01458-4"]}}