{"doi":"10.1021/jacs.5c13496","title":"Direct-to-Biology Enabled Molecular Glue Discovery","abstract":"High Resolution Image Download MS PowerPoint Slide Molecular glues powerfully control protein proximity but have largely eluded direct screening. A promising avenue for addressing this challenge lies within pinpointing the fundamental features for function-first identification of molecular gluing events. In the widely accepted mechanism, a molecular glue stabilizes two proteins within a ternary complex─here, we show how differences in affinity for ternary and binary complexes directly categorize glues from nonglues. We leverage these differences together with high-throughput chemical synthesis and affinity-selection mass-spectrometry to discover a molecular glue from a suite of over 20,000 crude chemical reaction mixtures. Orthogonal assays robustly support the identification of molecular glues via ternary complex stability. Our findings suggest that a roadmap for de novo molecular glue discovery lies within kinetic profiling of unpurified mixtures of small organic molecules against protein pairs.","journal":"Journal of the American Chemical Society","year":2025,"id":513142,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.945,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1217678,"name":"Jason Ochoada","orcid":null,"position":1,"is_corresponding":false},{"id":629050,"name":"Marisa Actis","orcid":null,"position":2,"is_corresponding":false},{"id":1186077,"name":"Kevin McGowan","orcid":"0000-0002-9542-3166","position":3,"is_corresponding":false},{"id":627484,"name":"Jamie Jarusiewicz","orcid":"0000-0003-4815-1505","position":4,"is_corresponding":false},{"id":328020,"name":"Satoshi Yoshimura","orcid":"0000-0002-4756-8790","position":5,"is_corresponding":false},{"id":1374170,"name":"Logan McGrath","orcid":null,"position":6,"is_corresponding":false},{"id":1022139,"name":"Uma Neelakantan","orcid":null,"position":7,"is_corresponding":false},{"id":580441,"name":"Anup Aggarwal","orcid":"0000-0003-1937-964X","position":8,"is_corresponding":false},{"id":501998,"name":"Anand Mayasundari","orcid":null,"position":9,"is_corresponding":false},{"id":1190034,"name":"Sarah M. Young","orcid":null,"position":10,"is_corresponding":false},{"id":407358,"name":"Meng Zhang","orcid":"0000-0003-4497-3253","position":11,"is_corresponding":false},{"id":33189,"name":"Lei Yang","orcid":"0000-0003-3718-2138","position":12,"is_corresponding":false},{"id":17221,"name":"Yong Li","orcid":"0000-0001-5617-1659","position":13,"is_corresponding":false},{"id":1374171,"name":"Shea Mercer","orcid":null,"position":14,"is_corresponding":false},{"id":91395,"name":"M. Madan Babu","orcid":"0000-0003-0556-6196","position":15,"is_corresponding":false},{"id":627488,"name":"Marcus Fischer","orcid":"0000-0002-7179-2581","position":16,"is_corresponding":false},{"id":381382,"name":"Brandon Young","orcid":"0000-0003-2973-2072","position":17,"is_corresponding":false},{"id":533596,"name":"Jun Yang","orcid":"0000-0002-4901-8530","position":18,"is_corresponding":false},{"id":627487,"name":"Gisele Nishiguchi","orcid":"0000-0003-2253-9325","position":19,"is_corresponding":false},{"id":267023,"name":"Anang A. Shelat","orcid":"0000-0002-6266-2910","position":20,"is_corresponding":false},{"id":531638,"name":"Daniel J. Blair","orcid":"0000-0002-2279-7538","position":21,"is_corresponding":false},{"id":1373493,"name":"Maowei Hu","orcid":"0000-0002-9317-3749","position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":null,"created_at":"2026-07-19T02:48:11.233009Z","pmid":"41443594","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}