Synthesis of a novel non‐diuretic, brain‐penetrating, ethacrynic acid analog and demonstration of its potent efficacy in orthotopic glioblastoma (GBM) models

• DOI: 10.1096/fasebj.31.1_supplement.178.1
• Publication Date: 2023-11-26T17:16:59Z
• Authors: Hanumantha Rao Ma...; Surendra Reddy Pu...; SRIVENUGOPAL KALK...
• Keywords: Brain tumor; Temozolomide

The incidence of pediatric and adult brain tumors has continued to rise in the USA alkylating agent temozolomide remained sole choice chemotherapy these lethal malignancies. Therefore, there is a very urgent need design new, more effective brain‐penetrating drugs that can significantly advance survival tumor patients. We are highly interested exploiting elevated oxidative stress present gliomas have synthesized hydrophobic, non‐diuretic analog ethacrynic acid (EA) called KSS72 by removing carboxylate side chain. was selectively cytotoxic cancer cells pharmacokinetics following intravenous or oral administrations mice showed its excellent penetrance through blood‐brain‐barrier, accumulating at levels equivalent (TMZ) brain. In vitro assays measuring protein carbonyl content, GSH ROS generation, GSTpi enzyme activity others triggers redox imbalance inhibiting lowering antioxidant (GSH) reducing (NADPH) levels, leading significant elevation levels. also upregulation endoplasmic reticulum (ER) stress‐responsive proteins, activation MAPK, autophagy apoptotic pathways several cell lines. view multiple cytocidal events mediated ROS, we tested antitumor efficacy human GBM lines intracranial xenografts. SF‐188 expressing firefly luciferase were injected into just left bregma for development orthotopic nude mice. These given 25 mg/kg/day intraperitoneally 2 weeks. animals when imaged IVIS after luciferin injections complete lack all administered animals. H&E staining mouse sections confirmed total elimination KSS72. did not exert any toxicity on host tissues serum ALT AST altered. summary, conclude acting hugely promising non‐toxic anti‐glioma drug with potential enter clinical trials. Support Funding Information CPRIT grant RP130266 KSS.