2. Academic Validation
  3. Preclinical Development of Brain Permeable ERβ Agonist for the Treatment of Glioblastoma

Preclinical Development of Brain Permeable ERβ Agonist for the Treatment of Glioblastoma

  • Mol Cancer Ther. 2023 Nov 1;22(11):1248-1260. doi: 10.1158/1535-7163.MCT-23-0031.
Uday P Pratap 1 2,  Michael Tidwell 3,  Henriette U Balinda 4,  Nicholas A Clanton 3,  Xue Yang 1 5,  Suryavathi Viswanadhapalli 1 2,  Gangadhara R Sareddy 1 2,  Dong Liang 6,  Huan Xie 6,  Yidong Chen 7 8,  Zhao Lai 7 9,  Rajeshwar R Tekmal 1 2,  Stanton F McHardy 3,  Andrew J Brenner 2 4,  Ratna K Vadlamudi 1 2 10
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas.
  • 2 Mays Cancer Center, University of Texas Health San Antonio, San Antonio, Texas.
  • 3 Department of Chemistry, Center for Innovative Drug Discovery, University of Texas Health San Antonio, Texas.
  • 4 Hematology & Oncology, University of Texas San Antonio, Texas.
  • 5 Department of Obstetrics and Gynecology, Second Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China.
  • 6 College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas.
  • 7 Greehey Children's Cancer Research Institute, University of Texas Health San Antonio, San Antonio, Texas.
  • 8 Department of Population Health Sciences, University of Texas Health San Antonio, San Antonio, Texas.
  • 9 Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, Texas.
  • 10 Audie L. Murphy South Texas Veterans Health Care System, San Antonio, Texas.
PMID: 37493258 DOI: 10.1158/1535-7163.MCT-23-0031
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.

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