Inhibition of the angiotensin II type 2 receptor AT 2 R is a novel therapeutic strategy for glioblastoma

• DOI: 10.1073/pnas.2116289119
• Publication Date: 2022-08-02T17:58:48Z
• Authors: Richard Perryman; Alexander Renzieh...; Hamidreza Shaye; Androniki D. Kost...; Antonis D. Tsiail...; Thomas Thorne; Maria V. Chatziat...; Gregory B. Sivola...; Mohamed Ahmed El ...; Gye Won Han; Barbara Zarzycka; Vsevolod Katritch; Guillaume Lebon; Cristiana Lo Nigro; Laura Lattanzio; Sophie V. Morse; James J. Choi; Kevin O’Neill; Zoi Kanaki; Apostolos Klinakis; Tim Crook; Vadim Cherezov; Andreas G. Tzakos; Nelofer Syed
• Keywords: Growth inhibition

Glioblastoma (GBM) is an aggressive malignant primary brain tumor with limited therapeutic options. We show that the angiotensin II (AngII) type 2 receptor (AT R) a target for GBM and AngII, endogenously produced in cells, promotes proliferation through AT R. repurposed EMA401, R antagonist originally developed as peripherally restricted analgesic, showed it inhibits of R-expressing spheroids blocks their invasiveness angiogenic capacity. The crystal structure bound to EMA401 was determined revealed be active-like conformation helix-VIII blocking G-protein or β-arrestin recruitment. architecture interactions differ drastically from complexes other relevant compounds. To enhance central nervous system (CNS) penetration we exploited design angiopep-2–tethered derivative, A3E. A3E exhibited enhanced CNS penetration, leading reduced volume, inhibition proliferation, increased levels apoptosis orthotopic xenograft model GBM.