{"doi":"10.1016/j.chembiol.2024.06.012","title":"A highly potent bi-thiazole inhibitor of LOX rewires collagen architecture and enhances chemoresponse in triple-negative breast cancer","abstract":"Lysyl oxidase (LOX) is upregulated in highly stiff aggressive tumors, correlating with metastasis, resistance, and worse survival; however, there are currently no potent, safe, and orally bioavailable small molecule LOX inhibitors to treat these aggressive desmoplastic solid tumors in clinics. Here we discovered bi-thiazole derivatives as potent LOX inhibitors by robust screening of drug-like molecules combined with cell/recombinant protein-based assays. Structure-activity relationship analysis identified a potent lead compound (LXG6403) with ∼3.5-fold specificity for LOX compared to LOXL2 while not inhibiting LOXL1 with a competitive, time- and concentration-dependent irreversible mode of inhibition. LXG6403 shows favorable pharmacokinetic properties, globally changes ECM/collagen architecture, and reduces tumor stiffness. This leads to better drug penetration, inhibits FAK signaling, and induces ROS/DNA damage, G1 arrest, and apoptosis in chemoresistant triple-negative breast cancer (TNBC) cell lines, PDX organoids, and in vivo. Overall, our potent and tolerable bi-thiazole LOX inhibitor enhances chemoresponse in TNBC, the deadliest breast cancer subtype.","journal":"Cell chemical biology","year":2024,"id":421977,"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":28,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9487,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":231086,"name":"Özge Saatci","orcid":"0000-0002-0124-044X","position":1,"is_corresponding":false},{"id":881674,"name":"Abdol-Hossein Rezaeian","orcid":"0000-0002-8826-2157","position":2,"is_corresponding":false},{"id":477175,"name":"C.N.R. Rao","orcid":"0000-0003-2451-0139","position":3,"is_corresponding":false},{"id":1215476,"name":"Chad Beneker","orcid":null,"position":4,"is_corresponding":false},{"id":1215477,"name":"K N Sreenivas","orcid":null,"position":5,"is_corresponding":false},{"id":497468,"name":"Harrison Taylor","orcid":"0000-0002-0369-789X","position":6,"is_corresponding":false},{"id":1075392,"name":"Breanna Pederson","orcid":null,"position":7,"is_corresponding":false},{"id":417435,"name":"Ioulia Chatzistamou","orcid":"0000-0002-6632-8469","position":8,"is_corresponding":false},{"id":353568,"name":"Brian Buckley","orcid":"0000-0001-7336-4321","position":9,"is_corresponding":false},{"id":396953,"name":"Susan M. Lessner","orcid":"0000-0002-8409-5216","position":10,"is_corresponding":false},{"id":377097,"name":"Peggi M. Angel","orcid":"0000-0002-4436-555X","position":11,"is_corresponding":false},{"id":759421,"name":"Campbell McInnes","orcid":"0000-0002-5592-9082","position":12,"is_corresponding":false},{"id":231105,"name":"Özgür Şahin","orcid":"0000-0002-8033-7089","position":13,"is_corresponding":false},{"id":987671,"name":"Metin Çetįn","orcid":"0000-0001-9963-8407","position":0,"is_corresponding":true}],"reference_count":79,"raw_metadata":null,"created_at":"2026-07-19T01:57:41.370244Z","pmid":"39043186","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":[]}