{"doi":"10.1073/pnas.2116289119","title":"Inhibition of the angiotensin II type 2 receptor AT <sub>2</sub> R is a novel therapeutic strategy for glioblastoma","abstract":"Glioblastoma (GBM) is an aggressive malignant primary brain tumor with limited therapeutic options. We show that the angiotensin II (AngII) type 2 receptor (AT 2 R) is a therapeutic target for GBM and that AngII, endogenously produced in GBM cells, promotes proliferation through AT 2 R. We repurposed EMA401, an AT 2 R antagonist originally developed as a peripherally restricted analgesic, for GBM and showed that it inhibits the proliferation of AT 2 R-expressing GBM spheroids and blocks their invasiveness and angiogenic capacity. The crystal structure of AT 2 R bound to EMA401 was determined and revealed the receptor to be in an active-like conformation with helix-VIII blocking G-protein or β-arrestin recruitment. The architecture and interactions of EMA401 in AT 2 R differ drastically from complexes of AT 2 R with other relevant compounds. To enhance central nervous system (CNS) penetration of EMA401, we exploited the crystal structure to design an angiopep-2–tethered EMA401 derivative, A3E. A3E exhibited enhanced CNS penetration, leading to reduced tumor volume, inhibition of proliferation, and increased levels of apoptosis in an orthotopic xenograft model of GBM.","journal":"Proceedings of the National Academy of Sciences","year":2022,"id":250045,"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":27,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9552,"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":891448,"name":"Alexander Renziehausen","orcid":"0000-0002-6304-0291","position":1,"is_corresponding":false},{"id":891449,"name":"Hamidreza Shaye","orcid":"0000-0002-8670-1259","position":2,"is_corresponding":false},{"id":892209,"name":"Androniki D. 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El Mubarak","orcid":"0000-0002-2575-3565","position":8,"is_corresponding":false},{"id":266169,"name":"Gye Won Han","orcid":"0000-0003-4107-835X","position":9,"is_corresponding":false},{"id":891454,"name":"Barbara Zarzycka","orcid":"0000-0002-7202-5317","position":10,"is_corresponding":false},{"id":40489,"name":"Vsevolod Katritch","orcid":"0000-0003-3883-4505","position":11,"is_corresponding":false},{"id":891455,"name":"Guillaume Lebon","orcid":"0000-0003-1162-5148","position":12,"is_corresponding":false},{"id":891456,"name":"Cristiana Lo Nigro","orcid":"0000-0002-3615-2431","position":13,"is_corresponding":false},{"id":892211,"name":"Laura Lattanzio","orcid":null,"position":14,"is_corresponding":false},{"id":891457,"name":"Sophie V. Morse","orcid":"0000-0001-5184-0200","position":15,"is_corresponding":false},{"id":891458,"name":"James J. 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