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Preclinical Development of Brain Permeable ERβ Agonist for the Treatment of Glioblastoma
Uday P Pratap1,2, Michael Tidwell3, Henriette U Balinda4
1Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas.
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 (ERβ) has been demonstrated to exert antitumor functions in GBM. The lack of potent, selective, and brain permeable ERβ agonist to promote its antitumor action is limiting the therapeutic promise of ERβ. In this study, we discovered that Indanone and tetralone-keto or hydroxyl oximes are a new class of ERβ agonists. Because of its high activity in ERβ reporter assays, specific binding to ERβ 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 ERβ than ERα (40-fold). Treatment with CIDD-0149897 markedly reduced GBM cell viability with an IC50 of ∼7 to 15 μmol/L, while having little to no effect on ERβ-KO cells and normal human astrocytes. Further, CIDD-0149897 treatment enhanced expression of known ERβ 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 ERβ agonist, offering patients with GBM a potential means of improving survival.
Insights
A new compound, CIDD-0149897, acts as an estrogen receptor beta (ERβ) agonist. This discovery offers a potential new treatment for glioblastoma (GBM) by inhibiting tumor growth and improving survival rates.
Area of Science:
- Neuro-oncology
- Endocrinology
- Medicinal Chemistry
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with poor prognosis.
- Estrogen receptor beta (ERβ) shows antitumor potential in GBM.
- Lack of selective ERβ agonists limits therapeutic development.
Purpose of the Study:
- To identify and characterize novel, selective, and brain-permeable ERβ agonists for GBM therapy.
- To evaluate the efficacy of a new compound, CIDD-0149897, in preclinical GBM models.
Main Methods:
- Screening of compound libraries to identify ERβ agonists.
- In vitro assays to assess compound selectivity, cytotoxicity, and gene expression.
- In vivo studies in GBM xenograft and orthotopic models.
- Pharmacokinetic and toxicity assessments.
Main Results:
- CIDD-0149897 identified as a potent and selective ERβ agonist (40-fold selective over ERα).
- CIDD-0149897 reduced GBM cell viability, enhanced ERβ target gene expression, and promoted apoptosis.
- Compound demonstrated good brain bioavailability and tolerability in mice.
- CIDD-0149897 significantly inhibited tumor growth and extended survival in GBM models.
Conclusions:
- CIDD-0149897 represents a new class of ERβ agonists with therapeutic potential for GBM.
- The compound's efficacy and pharmacokinetic profile support its further development for glioblastoma treatment.
