{"doi":"10.1038/s42003-025-08545-3","title":"Connecting chemical structure to single cell signaling profiles","abstract":"A challenge in chemical biology is to study structure-activity relationships (SAR) in vivo in cells. Multiplexed activity profiling (MAP), developed for natural product discovery, is well-suited to address this challenge as it is high throughput, singlecell, and measures multiple hallmark cellular functions. Applying MAP while systematically varying molecular structure (SAR-MAP) could reveal previously unappreciated activity within chemical families and prioritize candidate molecules for further characterization. Here we use SAR-MAP to identify structural features responsible for specific bioactivities of the natural product family, rocaglates. MV411 leukemia cells and healthy human leukocytes are selected for proof-of-concept screening. Testing 600 representative molecules using MAP classifies roughly half of tested rocaglates (9 of 19) as bioactive. SAR-MAP elucidates a methoxy substituent on select rocaglate pyrimidinones as responsible for a desirable anti-leukemia activity. Thus, SAR-MAP can be immediately applied to identify structural variations driving natural product activity in cell lines and primary human cells.","journal":"Communications Biology","year":2025,"id":545695,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9486,"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":818261,"name":"Madeline Hayes","orcid":"0000-0003-3684-9885","position":1,"is_corresponding":false},{"id":1168552,"name":"Laura C. Geben","orcid":"0000-0003-0604-4808","position":2,"is_corresponding":false},{"id":369564,"name":"Rebecca A. Ihrie","orcid":"0000-0003-0439-0141","position":3,"is_corresponding":false},{"id":275156,"name":"Lauren E. Brown","orcid":"0000-0001-9489-484X","position":4,"is_corresponding":false},{"id":275161,"name":"John A. Porco","orcid":"0000-0002-2991-5680","position":5,"is_corresponding":false},{"id":480936,"name":"Jonathan M. Irish","orcid":"0000-0001-9428-8866","position":6,"is_corresponding":false},{"id":1142988,"name":"Hannah L. Thirman","orcid":"0000-0002-3735-9995","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:53:27.751050Z","pmid":"40745386","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":[]}