{"doi":"10.1039/d5md00625b","title":"Schweinfurthins and their analogues are highly selective cellular probes for oxysterol-binding protein (OSBP)","abstract":"which display a unique cytotoxicity profile in human cancer cell lines with low nanomolar potency. Their known target is the sterol transport protein (STP) oxysterol-binding protein (OSBP), a key mediator and regulator of lipid transport between the endoplasmic reticulum (ER) and the trans-Golgi network (TGN). However, until now the underlying structure-activity relationships (SAR), as well as the cellular toxicity-target engagement relationships of SWs towards OSBP have not been well-studied. In this study, we present the first comprehensive SAR and selectivity study by characterizing 59 SW analogues utilizing our STP screening panel. Complementary detailed docking studies shine light on the SW-OSBP interactions and unravel amino acid residues critical for potent binding to OSBP. Additionally, we demonstrate cellular target engagement and correlate cancer cell cytotoxicity with Golgi fragmentation as a phenotypic consequence of OSBP inhibition by selected SW analogues. Therefore, this study will pave the way for more focused investigations and therapeutic applications of OSBP inhibitors.","journal":"RSC Medicinal Chemistry","year":2025,"id":548055,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9598,"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":1440800,"name":"Nianzhe He","orcid":"0000-0003-1871-3896","position":1,"is_corresponding":false},{"id":1440801,"name":"M. M. Madsen","orcid":"0009-0000-2460-7104","position":2,"is_corresponding":false},{"id":1440802,"name":"Mogens Brøndsted Nielsen","orcid":"0000-0001-8377-0788","position":3,"is_corresponding":false},{"id":1263079,"name":"Hogan P. Bryce-Rogers","orcid":"0000-0002-3186-9601","position":4,"is_corresponding":false},{"id":994247,"name":"Samantha C. Waterworth","orcid":"0000-0001-6436-0142","position":5,"is_corresponding":false},{"id":472109,"name":"Jeffrey D. Neighbors","orcid":"0000-0002-0698-4181","position":6,"is_corresponding":false},{"id":971591,"name":"David P. Stockdale","orcid":null,"position":7,"is_corresponding":false},{"id":1440803,"name":"Michael P. Callahan","orcid":"0000-0001-6743-0230","position":8,"is_corresponding":false},{"id":1441281,"name":"Nolan R. Mente","orcid":null,"position":9,"is_corresponding":false},{"id":519338,"name":"David F. Wiemer","orcid":"0000-0002-4881-8544","position":10,"is_corresponding":false},{"id":445219,"name":"John A. Beutler","orcid":"0000-0002-4646-1924","position":11,"is_corresponding":false},{"id":1263081,"name":"Luca Laraia","orcid":"0000-0001-6692-3412","position":12,"is_corresponding":false},{"id":1263078,"name":"Laura Depta","orcid":"0000-0002-4076-7316","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-19T02:53:53.962932Z","pmid":"41280340","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":[]}