{"doi":"10.1101/2020.04.17.047555","title":"Topsentinol L Trisulfate, a new Marine Natural Product, that Targets Basal-like and Claudin-low Breast Cancers","abstract":"ABSTRACT Background Breast cancer is a heterogeneous disease. Genomic studies have revealed five different intrinsic subtypes - Luminal A, Luminal B, HER2-enriched, Claudin-low, and Basal-like. Patients diagnosed with Basal-like or Claudin-low breast cancer (BL-CL) suffer from poor prognosis and limited treatment options. Hence, there is an urgent need to identify a new therapeutic lead that can benefit patients with BL-CL breast cancer. Methods We used a step-wise screening approach to screen 2778 HP20 fractions from our Marine Invertebrate Compound Library (MICL) to identify compounds that specifically target BL-CL breast cancer. We also performed biochemical investigations to study the effect of the compound in the signaling pathway. Finally, we generated a drug response gene-expression signature and projected it against a human tumor panel of 12 different cancer types to identify other cancer types sensitive to the compound. Results We identified a previously unreported trisulfated sterol, topsentinol L trisulfate (TLT) that exhibits increased efficacy against BL-CL relative to Luminal/HER2+ breast cancer. Biochemical investigation of the effects of TLT on BL-CL revealed its ability to inhibit activation of AMPK and CHK1 and promote activation of p38. The importance of targeting AMPK and CHK1 in BL-CL was validated by treating a panel of breast cancer cell lines with known small molecule inhibitors of AMPK (Dorsomorphin) and CHK1 (Ly2603618) and recording the increased effectiveness against BL-CL compared to Luminal/HER2+ breast cancer. The TLT sensitivity gene-expression signature identified breast and bladder cancer as the most sensitive to TLT while glioblastoma multiforme as least sensitive. Conclusions Our study identified TLT, a previously uncharacterized trisulfated sterol, as a potential therapeutic selective against BL-CL. Our results also showed that inhibition of AMPK and/or CHK1 might be an effective therapy in BL-CL.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":129403,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9509,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":38273,"name":"Thomas E. Smith","orcid":"0000-0002-4031-7753","position":1,"is_corresponding":false},{"id":566453,"name":"Gajendra Shrestha","orcid":"0000-0001-6525-7913","position":2,"is_corresponding":false},{"id":489778,"name":"Stephen Piccolo","orcid":"0000-0003-2001-5640","position":3,"is_corresponding":false},{"id":580974,"name":"Mary Kay Harper","orcid":null,"position":4,"is_corresponding":false},{"id":580975,"name":"Ryan M. Van Wagoner","orcid":null,"position":5,"is_corresponding":false},{"id":580623,"name":"Zhenyu Lu","orcid":"0000-0003-0420-437X","position":6,"is_corresponding":false},{"id":580976,"name":"Ashlee R. Venancio","orcid":null,"position":7,"is_corresponding":false},{"id":580624,"name":"Chris M. Ireland","orcid":"0009-0002-4079-1567","position":8,"is_corresponding":false},{"id":449639,"name":"Andrea H. Bild","orcid":"0000-0001-7906-6675","position":9,"is_corresponding":false},{"id":393343,"name":"Philip J. Moos","orcid":"0000-0002-8223-442X","position":10,"is_corresponding":false},{"id":580973,"name":"Nader N. El-Chaar","orcid":null,"position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":null,"created_at":"2026-07-18T23:15:45.920615Z","pmid":null,"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":[]}