LAUSR

Significance The prognosis for patients with glioblastoma (GBM) remains poor and novel therapeutic approaches to address this unmet clinical need are urgently required. Here we show that angiotensin II (AngII), a peptide involved in salt and water balance, is produced endogenously by GBM cells and drives proliferation via the type 2 receptor of AngII (AT2R). We repurposed a peripherally restricted AT2R antagonist, originally developed for the treatment of neuropathic pain, through the generation of a compound, A3E, that has greater efficacy in vitro and optimized central nervous system penetration and efficacy in vivo with minimal toxicity. This study demonstrates that inhibition of AT2R is a promising candidate target for systemic therapy of GBM.