{"doi":"10.1021/jacs.3c05161","title":"Structure-Based Optimization of Covalent, Small-Molecule Stabilizers of the 14-3-3σ/ERα Protein–Protein Interaction from Nonselective Fragments","abstract":"High Resolution Image Download MS PowerPoint Slide The stabilization of protein–protein interactions (PPIs) has emerged as a promising strategy in chemical biology and drug discovery. The identification of suitable starting points for stabilizing native PPIs and their subsequent elaboration into selective and potent molecular glues lacks structure-guided optimization strategies. We have previously identified a disulfide fragment that stabilized the hub protein 14-3-3σ bound to several of its clients, including ERα and C-RAF. Here, we show the structure-based optimization of the nonselective fragment toward selective and highly potent small-molecule stabilizers of the 14-3-3σ/ERα complex. The more elaborated molecular glues, for example, show no stabilization of 14-3-3σ/C-RAF up to 150 μM compound. Orthogonal biophysical assays, including mass spectrometry and fluorescence anisotropy, were used to establish structure–activity relationships. The binding modes of 37 compounds were elucidated with X-ray crystallography, which further assisted the concomitant structure-guided optimization. By targeting specific amino acids in the 14-3-3σ/ERα interface and locking the conformation with a spirocycle, the optimized covalent stabilizer 181 achieved potency, cooperativity, and selectivity similar to the natural product Fusicoccin-A. This case study showcases the value of addressing the structure, kinetics, and cooperativity for molecular glue development.","journal":"Journal of the American Chemical Society","year":2023,"id":322820,"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":39,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9473,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1029672,"name":"Emira J. Visser","orcid":"0000-0002-6098-8060","position":1,"is_corresponding":false},{"id":1037497,"name":"Edmee Vandenboorn","orcid":null,"position":2,"is_corresponding":false},{"id":1036999,"name":"Sheng Chen","orcid":"0000-0001-7764-7097","position":3,"is_corresponding":false},{"id":490823,"name":"Priyadarshini Jaishankar","orcid":"0009-0005-2013-8941","position":4,"is_corresponding":false},{"id":1037498,"name":"Maurits Overmans","orcid":null,"position":5,"is_corresponding":false},{"id":1037499,"name":"Shubhankar Dutta","orcid":null,"position":6,"is_corresponding":false},{"id":984324,"name":"R. Jeffrey Neitz","orcid":"0000-0002-2247-9345","position":7,"is_corresponding":false},{"id":490827,"name":"Adam R. Renslo","orcid":"0000-0002-1240-2846","position":8,"is_corresponding":false},{"id":254398,"name":"Christian Ottmann","orcid":"0000-0001-7315-0315","position":9,"is_corresponding":false},{"id":1029675,"name":"Luc Brunsveld","orcid":"0000-0001-5675-511X","position":10,"is_corresponding":false},{"id":246284,"name":"Michelle R. Arkin","orcid":"0000-0002-9366-6770","position":11,"is_corresponding":false},{"id":230784,"name":"Markella Konstantinidou","orcid":"0000-0001-5972-4140","position":0,"is_corresponding":true}],"reference_count":77,"raw_metadata":null,"created_at":"2026-07-19T01:07:47.432636Z","pmid":"37676236","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":[]}