{"doi":"10.3389/fphar.2020.00974","title":"A Brain-Penetrating Hsp90 Inhibitor NXD30001 Inhibits Glioblastoma as a Monotherapy or in Combination With Radiation","abstract":"Glioblastoma multiforme (GBM) is a highly heterogeneous disease, which is initiated and sustained by various molecular alterations in an array of signal transduction pathways. Heat-shock protein 90 (Hsp90) is a molecular chaperone and is critically implicated in folding and activation of a diverse group of client proteins, many of which are key regulators for glioblastoma biology. We here assessed the anti-neoplastic efficacy of a novel brain-penetrating Hsp90 inhibitor NXD30001 as a monotherapy and combined with radiation in vitro and in vivo. Our results demonstrated that NXD30001 potently inhibited neurosphere formation, growth and survival of CD133+ GBM cells with the half maximal inhibitory concentration at low nanomolar range, but CD133- GBM cells were less sensitive to NXD30001. NXD30001 also increased radio-sensitivity in glioblastoma stem cells (GSCs) at suboptimal concentrations. Moreover, NXD30001 dose-dependently decreased phosphorylation levels of multiple Hsp90 client proteins which play key roles in GBM, such as EGFR, Akt, c-Myc and Notch1. In addition, NXD30001 could impair DNA damage response and endoplasmic reticulum stress response after radiotherapy by alteration of the related proteins expression. In a murine orthotopic model of human glioblastoma, NXD30001 marvelously induced tumor regression and extended median survival of tumor-bearing mice by approximately 20% when compared with the vehicle group (37 days vs 31 days, P<0.05). Radiotherapy solely increased median survival of tumor-bearing mice from 31 days to 38 days (P<0.05), while NXD30001 combined with radiation further extended survival to 43 days (P<0.05). We concluded that GSCs are more sensitive to NXD30001 than non-stem GBM cells, and NXD30001 in combination with radiation exerts better inhibitive effect in GBM progression than monotherapy.","journal":"Frontiers in Pharmacology","year":2020,"id":103249,"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":25,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9594,"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":504014,"name":"Yuanying Gong","orcid":null,"position":1,"is_corresponding":false},{"id":503184,"name":"Yufang Ma","orcid":"0000-0001-6672-3875","position":2,"is_corresponding":false},{"id":481955,"name":"Reid C. Thompson","orcid":null,"position":3,"is_corresponding":false},{"id":503185,"name":"Jialiang Wang","orcid":"0000-0001-7677-449X","position":4,"is_corresponding":false},{"id":503186,"name":"Zhixiang Cheng","orcid":"0000-0003-0867-685X","position":5,"is_corresponding":false},{"id":503187,"name":"Lixia Xue","orcid":"0000-0001-8807-9662","position":6,"is_corresponding":false},{"id":12579,"name":"Hao Chen","orcid":"0009-0001-6480-7976","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-18T22:42:17.920911Z","pmid":"32695001","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":[]}