{"doi":"10.1016/j.apsb.2022.03.023","title":"Preclinical studies of the triazolo[1,5-a]pyrimidine derivative WS-716 as a highly potent, specific and orally active P-glycoprotein (P-gp) inhibitor","abstract":"Multidrug resistance (MDR) is the main cause of clinical treatment failure and poor prognosis in cancer. Targeting P-glycoprotein (P-gp) has been regarded as an effective strategy to overcome MDR. In this work, we reported our preclinical studies of the triazolo[1,5-a]pyrimidine-based compound WS-716 as a highly potent, specific, and orally active P-gp inhibitor. Through direct binding to P-gp, WS-716 inhibited efflux function of P-gp and specifically reversed P-gp-mediated MDR to paclitaxel (PTX) in multiple resistant cell lines, without changing its expression or subcellular localization. WS-716 and PTX synergistically inhibited formation of colony and 3D spheroid, induced apoptosis and cell cycle arrest at G2/M phase in resistant SW620/Ad300 cells. In addition, WS-716 displayed minimal effect on the drug-metabolizing enzyme cytochrome P4503A4 (CYP3A4). Importantly, WS-716 increased sensitivity of both pre-clinically and clinically derived MDR tumors to PTX in vivo with the T/C value of 29.7% in patient-derived xenograft (PDX) models. Relative to PTX treatment alone, combination of WS-716 and PTX caused no obvious adverse reactions. Taken together, our preclinical studies revealed therapeutic promise of WS-716 against MDR cancer, the promising data warrant its further development for cancer therapy.","journal":"Acta Pharmaceutica Sinica B","year":2022,"id":243079,"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":35,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9546,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":327829,"name":"Qiu‐Xu Teng","orcid":null,"position":1,"is_corresponding":false},{"id":784979,"name":"Shuai Wang","orcid":"0000-0003-0718-1820","position":2,"is_corresponding":false},{"id":326822,"name":"Zi‐Ning Lei","orcid":"0000-0003-1696-8385","position":3,"is_corresponding":false},{"id":874778,"name":"Huihui Hu","orcid":"0000-0002-9418-2639","position":4,"is_corresponding":false},{"id":874779,"name":"Huifang Lv","orcid":"0000-0003-0008-3961","position":5,"is_corresponding":false},{"id":606768,"name":"Beibei Chen","orcid":"0000-0001-7772-5171","position":6,"is_corresponding":false},{"id":874780,"name":"Jianzheng Wang","orcid":"0000-0002-2292-3629","position":7,"is_corresponding":false},{"id":874781,"name":"Xiaojing Shi","orcid":"0000-0002-5792-1287","position":8,"is_corresponding":false},{"id":874782,"name":"Weifeng Xu","orcid":"0000-0001-6682-3075","position":9,"is_corresponding":false},{"id":95596,"name":"Hong‐Min Liu","orcid":"0000-0001-6771-9421","position":10,"is_corresponding":false},{"id":494429,"name":"Xiaobing Chen","orcid":"0000-0002-7463-7114","position":11,"is_corresponding":false},{"id":253755,"name":"Zhe‐Sheng Chen","orcid":"0000-0002-8289-097X","position":12,"is_corresponding":false},{"id":874783,"name":"Bin Yu","orcid":"0000-0002-7207-643X","position":13,"is_corresponding":false},{"id":875492,"name":"Saiqi Wang","orcid":null,"position":0,"is_corresponding":true}],"reference_count":61,"raw_metadata":null,"created_at":"2026-07-19T00:23:16.032700Z","pmid":"35967279","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":[]}