Preclinical Development of Brain Permeable ERß Agonist for the Treatment of Glioblastoma.
Mol Cancer Ther
; 22(11): 1248-1260, 2023 Nov 01.
Article
em En
| MEDLINE
| ID: mdl-37493258
ABSTRACT
Glioblastoma (GBM) is the most prevalent and aggressive type of adult brain tumors with low 5-year overall survival rates. Epidemiologic data suggest that estrogen may decrease brain tumor growth, and estrogen receptor beta (ERß) has been demonstrated to exert antitumor functions in GBM. The lack of potent, selective, and brain permeable ERß agonist to promote its antitumor action is limiting the therapeutic promise of ERß. In this study, we discovered that Indanone and tetralone-keto or hydroxyl oximes are a new class of ERß agonists. Because of its high activity in ERß reporter assays, specific binding to ERß in polar screen assays, and potent growth inhibitory activity in GBM cells, CIDD-0149897 was discovered as a possible hit by screening a library of compounds. CIDD-0149897 is more selective for ERß than ERα (40-fold). Treatment with CIDD-0149897 markedly reduced GBM cell viability with an IC50 of â¼7 to 15 µmol/L, while having little to no effect on ERß-KO cells and normal human astrocytes. Further, CIDD-0149897 treatment enhanced expression of known ERß target genes and promoted apoptosis in established and patient-derived GSC models. Pharmacokinetic studies confirmed that CIDD-0149897 has systemic exposure, and good bioavailability in the brain. Mice tolerated daily intraperitoneal treatment of CIDD-0149897 (50 mg/kg) with a 7-day repeat dosage with no toxicity. In addition, CIDD-0149897 treatment significantly decreased tumor growth in U251 xenograft model and extended the survival of orthotopic GBM tumor-bearing mice. Collectively, these findings pointed to CIDD-0149897 as a new class of ERß agonist, offering patients with GBM a potential means of improving survival.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Encefálicas
/
Glioblastoma
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article