DDDR-73. Preclinical evaluation of blood brain permeable, novel nicotinamide phosphoribosyl-transferase (NAMPT) inhibitor in gliomas

Abstract BACKGROUND Metabolic dysregulation is a hallmark of cancer, including gliomas. One key difference between normal and cancer cells is NAD generation, essential for energy metabolism, DNA repair, and redox balance. Glioma cells primarily rely on nicotinamide phosphoribosyltransferase (NAMPT) for NAD synthesis. This study tested the efficacy of RPT-E-36, RPT-E-50, and RPT-E-51—novel, orally bioavailable, brain-penetrant NAMPT inhibitors—in gliomas. These hyperbolic inhibitors were designed to selectively impair tumor cell viability while preserving NAMPT function in normal cells minimizing potential for toxicity. METHODS Efficacy was evaluated using CellTiter-Glo assays in molecularly heterogeneous, patient-derived glioma stem-like cells (GSCs), treated with or without inhibitors. Flow cytometry was used to quantify cell cycle changes and programmed cell death. Protein expression of key molecular markers was measured using Simple Western. For in vivo studies, athymic nude mice were intracranially implanted with GSC811-GFP-Luc cells and treated with 50 mg/kg or 100 mg/kg of inhibitors. Tumor growth, body weight, and survival were monitored, with efficacy assessed via Kaplan-Meier analysis. RESULTS RPT-E-36, RPT-E-50, and RPT-E-51 robustly inhibited proliferation in molecularly diverse GSC lines, without affecting normal human astrocytes or brain microvascular endothelial cells. RPT-E-50 emerged as the most potent of the three inhibitors, showing superior effects on both proliferation and induction of programmed cell death, prompting its selection for further in vivo and ex vivo evaluation. Preliminary findings in ongoing in vivo studies indicate a survival advantage with RPT-E-50 in a mouse intracranial xenograft model. Final in vivo and ex vivo glioma slice culture data will be reported. CONCLUSIONS Glioma proliferation and survival show significant dependence on NAMPT, which can be therapeutically targeted using novel NAMPT inhibitors. Ongoing studies aim to elucidate the mechanisms and therapeutic implications, supporting future clinical trials in glioblastoma.