{"doi":"10.3389/fphar.2021.620874","title":"OTS964, a TOPK Inhibitor, Is Susceptible to ABCG2-Mediated Drug Resistance","abstract":"OTS964 is a potent T-LAK cell-originated protein kinase (TOPK) inhibitor. Herein, we investigated the interaction of OTS964 and multidrug resistance (MDR)-associated ATP-binding cassette sub-family G member 2 (ABCG2). The cell viability assay indicated that the effect of OTS964 is limited in cancer drug-resistant and transfected cells overexpressing ABCG2. We found that the known ABCG2 transporter inhibitor has the ability to sensitize ABCG2-overexpressing cells to OTS964. In mechanism-based studies, OTS964 shows inhibitory effect on the efflux function mediated by ABCG2, and in turn, affects the pharmacokinetic profile of other ABCG2 substrate-drugs. Furthermore, OTS964 upregulates ABCG2 protein expression, resulting in enhanced resistance to ABCG2 substrate-drugs. The ATPase assay demonstrated that OTS964 stimulates ATPase activity of ABCG2 in a concentration-dependent manner. The computational molecular docking analysis combined with results from ATPase assay suggested that OTS964 interacts with drug-binding pocket of ABCG2 and has substrate-like behaviors. Thus, OTS964 is an MDR-susceptible agent due to its interactions with ABCG2, and overexpression of ABCG2 transporter may attenuate its therapeutic effect in cancer cells.","journal":"Frontiers in Pharmacology","year":2021,"id":189731,"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":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9579,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":256746,"name":"Zhuo‐Xun Wu","orcid":null,"position":1,"is_corresponding":false},{"id":326821,"name":"Jing‐Quan Wang","orcid":"0000-0003-4331-0482","position":2,"is_corresponding":false},{"id":327829,"name":"Qiu‐Xu Teng","orcid":null,"position":3,"is_corresponding":false},{"id":326822,"name":"Zi‐Ning Lei","orcid":"0000-0003-1696-8385","position":4,"is_corresponding":false},{"id":334607,"name":"Sabrina Lusvarghi","orcid":"0000-0003-1793-0450","position":5,"is_corresponding":false},{"id":334608,"name":"Suresh V. Ambudkar","orcid":"0000-0002-2639-4955","position":6,"is_corresponding":false},{"id":253755,"name":"Zhe‐Sheng Chen","orcid":"0000-0002-8289-097X","position":7,"is_corresponding":false},{"id":326827,"name":"Dong‐Hua Yang","orcid":"0000-0001-8649-5531","position":8,"is_corresponding":false},{"id":334606,"name":"Yuqi Yang","orcid":"0000-0002-7830-8238","position":0,"is_corresponding":true}],"reference_count":46,"raw_metadata":null,"created_at":"2026-07-18T23:49:18.604374Z","pmid":"33658942","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":[]}