New anti-glioblastoma metabolic compounds with high potential for Blood Brain Barrier penetration

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Glioblastomas are very aggressive tumors of the central nervous system (CNS) with a median patient survival of about 16 months. Therapeutic options for glioblastoma patients are very limited mostly because the majority of potential anti-cancer drugs do not cross the blood brain barrier (BBB). In addition, recently tested immunotherapies including immune checkpoint inhibitors, tumor vaccines, and adoptive cell therapies failed to produce a positive outcome in glioblastoma patients. Surprisingly, metabolic approaches including calorie restriction and ketogenic diet demonstrate promising results as supplemental therapies for glioblastoma patients. In this regard, multiple studies, including our research, show that a common lipid-lowering prodrug, fenofibrate (FF), triggers a severe energetic crisis in glioblastoma cells by compromising the function of Complex 1 of the electron transport chain (ETC), leading to the extensive glioblastoma cell death. However, FF does not cross the BBB and is quickly processed by blood and tissue esterases to fenofibric acid, which is a potent PPARµ agonist, no longer effective in killing glioblastoma cells. Therefore, we have made several chemical modifications in the FF molecular skeleton to construct a new family of drugs with high anti-glioblastoma potential. In this proposal, we attempt to test the overall hypothesis that specific chemical modification/s in the common molecular skeleton of FF, benzyl-phenoxy-acetamide (BPA), will result in a new anti-glioblastoma metabolic drug/s that are stable, capable of crossing the BBB, and effective in triggering glioblastoma cell death at low µM concentrations. Our preliminary results indicate that two new drug candidates designated here, as MT1 and MT3, have very promising characteristics for BBB penetration. To evaluate these compounds, we have developed a comprehensive experimental approach consisting of: a) computational modeling of the BPA molecular structure by applying the Central Nervous System – Multiparameter Optimization (CNS-MPO) algorithm; b) development of the most effective strategy for synthesis and testing of chemical integrity and purity of the new compound; c) in vitro testing for glioblastoma cytotoxicity and the mechanism of action; and d) Pharmacokinetic analyses of the compound bioavailability, maximal tolerated dose (MTD) and anti-glioblastoma efficacy in highly relevant animal models.