Inhibition of the angiotensin II type 2 receptor AT2R is a novel therapeutic strategy for glioblastoma
File(s)
Published version
Author(s)
Perryman, Richard
Renziehausen, Alexander
Shaye, Hamidreza
Kostagianni, Androniki D
Tsiailanis, Antonis D
Type
Journal Article
Abstract
Glioblastoma (GBM) is an aggressive malignant primary brain tumor with limited therapeutic options. We show that the angiotensin II (AngII) type 2 receptor (AT2R) is a novel therapeutic target for GBM and that AngII, endogenously produced in GBM cells, promotes proliferation through AT2R. We repurposed EMA401, an AT2R antagonist originally developed as a peripherally restricted analgesic, for GBM and showed that it inhibits the proliferation of AT2R-expressing GBM spheroids and blocks their invasiveness and angiogenic capacity. The crystal structure of AT2R 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 AT2R differ drastically from complexes of AT2R 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.
Date Issued
2023-08-02
Date Acceptance
2022-05-27
Citation
Proceedings of the National Academy of Sciences of USA, 2023, 119 (32)
ISSN
0027-8424
Publisher
National Academy of Sciences
Journal / Book Title
Proceedings of the National Academy of Sciences of USA
Volume
119
Issue
32
Copyright Statement
© 2022 the Author(s). Published by PNAS. This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
Identifier
https://www.pnas.org/doi/full/10.1073/pnas.2116289119
Publication Status
Published
Article Number
ARTN e2116289119