{"doi":"10.31083/j.fbl2701005","title":"ABCB1 limits the cytotoxic activity of TAK-243, an inhibitor of the ubiquitin-activating enzyme UBA1","abstract":"BACKGROUND: One of the major concerns of cancer therapy is the emergence of multidrug resistance (MDR). The MDR-associated ATP-binding cassette sub-family B member 1 (ABCB1) transporter is established to mediate resistance against numerous anticancer drugs. In this study, we demonstrated that the Ubiquitin-like modifier activating enzyme 1 (UBA1) inhibitor TAK-243 is transported by the ABCB1. METHODS: MTT assay was performed to evaluate the cytotoxicity of TAK-243. Western blot was carried out to investigate if TAK-243 affect to ABCB1 protein expression in cancer cells. High Performance Liquid Chromatography (HPLC) and ATPase assay were carried out to confirm TAK-243 as an ABCB1 substrate. [3H]-paclitaxel accumulation assay was used to determine the MDR reversal effect of TAK-243. Computational docking analysis was performed to investigate the drug-transporter binding position. RESULTS: The cytotoxicity profile showed that TAK-243 was less effective in ABCB1-overexpressing cells than in the parental cells, but pharmacological inhibition or knockout the gene of ABCB1 was able to reverse TAK-243 resistance. Furthermore, TAK-243 potently stimulated ABCB1 ATPase activity and the HPLC analysis revealed that TAK-243 accumulation was significantly reduced in ABCB1-overexpressing cells. Finally, the computational docking analysis indicates a high binding affinity between TAK-243 and human ABCB1 transporter. CONCLUSIONS: data characterized TAK-243 as a substrate of ABCB1, which may predict limited anticancer effect of this compound in drug resistant tumors.","journal":"Frontiers in Bioscience-Landmark","year":2022,"id":280548,"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":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.962,"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":334606,"name":"Yuqi Yang","orcid":"0000-0002-7830-8238","position":1,"is_corresponding":false},{"id":326822,"name":"Zi‐Ning Lei","orcid":"0000-0003-1696-8385","position":2,"is_corresponding":false},{"id":676304,"name":"Silpa Narayanan","orcid":null,"position":3,"is_corresponding":false},{"id":326821,"name":"Jing‐Quan Wang","orcid":"0000-0003-4331-0482","position":4,"is_corresponding":false},{"id":327829,"name":"Qiu‐Xu Teng","orcid":null,"position":5,"is_corresponding":false},{"id":739728,"name":"Megumi Murakami","orcid":"0000-0002-3920-2166","position":6,"is_corresponding":false},{"id":334608,"name":"Suresh V. Ambudkar","orcid":"0000-0002-2639-4955","position":7,"is_corresponding":false},{"id":955022,"name":"Fengfeng Ping","orcid":"0000-0003-4444-4976","position":8,"is_corresponding":false},{"id":253755,"name":"Zhe‐Sheng Chen","orcid":"0000-0002-8289-097X","position":9,"is_corresponding":false},{"id":256746,"name":"Zhuo‐Xun Wu","orcid":null,"position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-19T00:29:03.247347Z","pmid":"35090310","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":[]}