Abstract 4310: Novel analogues of indanone and tetralone-keto oximes as potent estrogen receptor beta agonists for treating GBM

Abstract Background: Glioblastoma (GBM) is the most common and aggressive brain tumor, with a poor 5-year survival rate. Epidemiological studies suggest that estrogen receptor beta (ERb) may inhibit brain tumor growth, highlighting the potential therapeutic role of ERb. However, the lack of potent, selective, and brain-permeable ERb ligands has limited the clinical application of ERb-based therapies. We recently identified indanone and tetralone-keto oximes as promising ERb agonists. To further optimize these compounds, we employed a structure-based drug design strategy, utilizing existing X-ray structural data to guide the development of novel ligands targeting the ERb-ligand-binding domain. The objective of this study is to design and develop a new class of ERb agonists that can cross the blood-brain barrier and offer an effective treatment option for GBM. Methods: To improve CIDD-0149897 potency and comprehend pharmacophores, we designed and synthesized 99 more analogues. The selectivity of CIDD-0149897 analogues was determined using ERb and ERa reporter assays. CIDD-0149897 analogues were examined for cell viability using CellTiter-Glo and apoptosis using Annexin V and Western blotting, ionizing radiation, RT-qPCR, comet assays, and mass spec analysis were used for mechanistic research. UTSA's Center for Innovative Drug Discovery (CIDD) pre-clinical pharmacology core performed in vitro ADME studies. The ERb agonist was tested in vivo using orthotopic patient-derived xenografts. Results: Our analysis of new CIDD-0149897 analogues identified four optimized ERb agonists with improved specificity and potency. ADME studies showed these agonists have 20-50-times better aqueous solubility than CIDD-0149897, with excellent plasma stability. Microsomal and hepatocyte stability varied, with alcohol analogues being more stable. The MDCK-hMDR1 KO cell line shows low to moderate mono-directional permeability and minimal pGP efflux. Treatment with optimized ERb agonists dramatically reduced neurosphere formation, stemness marker expression, and promoted apoptosis in patient-derived GSC model cells. Mass spec data analysis showed that ERb binding proteins are involved in DNA repair and damage response, replication, and G1 checkpoint. In combination with Temozolomide, ERb agonists sensitized GSCs, increased DNA damage, and inhibited neurosphere formation. Comet assay demonstrated enhanced DNA damage in the combination group compared to single agent treatment. The lead compound CIDD-0169124 significantly reduced tumor volume in orthotopic model compared to the vehicle. CIDD-0169124 also improved TMZ-treated GSC tumor-bearing mouse survival relative to vehicle or TMZ monotherapy in an orthotopic GBM model. Conclusion: These findings showed that CIDD-0169124 is a potent ERb agonist that can be used with existing chemotherapies to improve GBM patients' survival. Citation Format: Uday P. Pratap, Michael Tidwell, Annabel Maciolek, Luca De Angelis, Sridharan Jayamohan, Jessica D. Johnson, Khaled Mohamed Nassar, Karinel Nieves-Merced, Henriette U. Balinda, Peter LoCoco, Joseph Boerma, Suryavathi Viswanadhapalli, Gangadhara Reddy Sareddy, Nicholas Clanton, Stanton McHardy, Andrew Brenner, Ratna K. Vadlamudi. Novel analogues of indanone and tetralone-keto oximes as potent estrogen receptor beta agonists for treating GBM [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4310.