Abstract B031: A brain penetrant Nicotinamide-adenine dinucleotide mimetic impedes de novo guanylate synthesis and glioblastoma growth

作者：Yu-Jung Chen, Swathi V. Iyer, Chun-Cheng Hsieh, Tao Wang, Jing Li, Michelle Lien, Mungunsarnai Ganbold, Xuanhua Xie, Chenura D. Jayewickreme, Sean F. Brady, Kyun Lim, Luis F. Parada · 发表于：Cancer Research · 年份：2024 · DOI：10.1158/1538-7445.brain23-b031 · 研究领域：PARP inhibition in cancer therapy、RNA Interference and Gene Delivery、CRISPR and Genetic Engineering

Abstract Glioblastoma is a malignant disease with dire prognosis and in urgent need of improved therapeutics. We identify a small compound, Gliocidin, that kills glioblastoma cells while sparing replicative mouse embryonic fibroblasts. Gliocidin activity reveals a de novo purine synthesis pathway metabolic vulnerability in glioblastoma caused by indirect inhibition of inosine monophosphate dehydrogenase 2 (IMPDH2). Gliocidin mediated IMPDH2 blockade reduces intracellular guanine nucleotide levels causing nucleotide imbalance, replication stress, and tumor cell death. Gliocidin is a prodrug anabolized into its tumoricidal metabolite by the enzyme nicotinamide nucleotide adenylyltransferase (NMNAT1) of the NAD+ salvage pathway. In vivo, Gliocidin penetrates the blood brain barrier and extends orthotopic murine GBM mouse survival. The DNA alkylating agent, Temozolomide (TMZ), induces Nmnat1 expression causing a synergistic tumor killing effect and additional survival benefit in patient-derived xenograft (PDX) orthotopic mouse models. This study brings Gliocidin to light as a prodrug that can improve the survival of GBM patients. Citation Format: Yu-Jung Chen, Swathi V. Iyer, Chun-Cheng David Hsieh, Tao Wang, Jing Li, Michelle C. Lien, Mungunsarnai Ganbold, Xuanhua P. Xie, Chenura Jayewickreme, Sean F Brady, Kyun Lim, Luis F Parada. A brain penetrant Nicotinamide-adenine dinucleotide mimetic impedes de novo guanylate synthesis and glioblastoma growth [abstract]. In: Proceedings o...