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Inhibition of the angiotensin II type 2 receptor AT2R is a novel therapeutic strategy for glioblastoma.
- Source :
- Proceedings of the National Academy of Sciences of the United States of America; 8/9/2022, Vol. 119 Issue 32, p1-36, 48p
- Publication Year :
- 2022
-
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<subscript>2</subscript>R) is a therapeutic target for GBM and that AngII, endogenously produced in GBM cells, promotes proliferation through AT<subscript>2</subscript>R. We repurposed EMA401, an AT<subscript>2</subscript>R antagonist originally developed as a peripherally restricted analgesic, for GBM and showed that it inhibits the proliferation of AT<subscript>2</subscript>R-expressing GBM spheroids and blocks their invasiveness and angiogenic capacity. The crystal structure of AT<subscript>2</subscript>R bound to EMA401 was determined and revealed the receptor to be in an active-like conformation with helix-VIII blocking G-protein or ß-arrestin recruitment. The architecture and interactions of EMA401 in AT<subscript>2</subscript>R differ drastically from complexes of AT<subscript>2</subscript>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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 119
- Issue :
- 32
- Database :
- Complementary Index
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 158560518
- Full Text :
- https://doi.org/10.1073/pnas.2116289119