美国纪念斯隆凯特琳癌症中心Luis F. Parada团队近期取得重要工作进展，他们研究提出，Gliocidin是一种靶向胶质母细胞瘤的模拟烟酰胺前药。相关研究成果2024年11月20日在线发表于《自然》杂志上。

据介绍，胶质母细胞瘤是无法治愈的，迫切需要改进的治疗方法。

研究人员发现了一种小化合物，Gliocidin，它可以杀死胶质母细胞瘤细胞，同时保留非肿瘤复制细胞。Gliocidin活性通过间接抑制肌苷单磷酸脱氢酶2（IMPDH2）来靶向胶质母细胞瘤中的从头嘌呤合成脆弱性。IMPDH2阻断会降低细胞内鸟嘌呤核苷酸水平，导致核苷酸失衡、复制应激和肿瘤细胞死亡。

Gliocidin是一种前体药物，通过NAD?拯救通路中的烟酰胺核苷酸腺苷转移酶1（NMNAT1）酶的作用，被代谢为其具有肿瘤杀伤活性的代谢产物——gliocidin-腺嘌呤二核苷酸（GAD）。GAD和IMPDH2的冷冻电镜结构表明其进入、变形和阻断NAD⁺口袋。

在体内，胶质酸性蛋白穿透血脑屏障，延长原位胶质母细胞瘤小鼠的存活时间。DNA烷化剂替莫唑胺诱导Nmnat1表达，在原位患者来源的异种移植物模型中，引起协同肿瘤细胞杀伤和额外的生存益处。

总之，这一研究揭示了胶质酸作为一种前药，有可能提高胶质母细胞瘤患者的生存率。

附：英文原文

Title: Gliocidin is a nicotinamide-mimetic prodrug that targets glioblastoma

Author: Chen, Yu-Jung, Iyer, Swathi V., Hsieh, David Chun-Cheng, Li, Buren, Elias, Harold K., Wang, Tao, Li, Jing, Ganbold, Mungunsarnai, Lien, Michelle C., Peng, Yu-Chun, Xie, Xuanhua P., Jayewickreme, Chenura D., van den Brink, Marcel R. M., Brady, Sean F., Lim, S. Kyun, Parada, Luis F.

Issue&Volume: 2024-11-20

Abstract: Glioblastoma is incurable and in urgent need of improved therapeutics1. Here we identify a small compound, gliocidin, that kills glioblastoma cells while sparing non-tumour replicative cells. Gliocidin activity targets a de novo purine synthesis vulnerability in glioblastoma through indirect inhibition of inosine monophosphate dehydrogenase 2 (IMPDH2). IMPDH2 blockade reduces intracellular guanine nucleotide levels, causing nucleotide imbalance, replication stress and tumour cell death2. Gliocidin is a prodrug that is anabolized into its tumoricidal metabolite, gliocidin–adenine dinucleotide (GAD), by the enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) of the NAD+ salvage pathway. The cryo-electron microscopy structure of GAD together with IMPDH2 demonstrates its entry, deformation and blockade of the NAD+ pocket3. In vivo, gliocidin penetrates the blood–brain barrier and extends the survival of mice with orthotopic glioblastoma. The DNA alkylating agent temozolomide induces Nmnat1 expression, causing synergistic tumour cell killing and additional survival benefit in orthotopic patient-derived xenograft models. This study brings gliocidin to light as a prodrug with the potential to improve the survival of patients with glioblastoma.

DOI: 10.1038/s41586-024-08224-z

Source: https://www.nature.com/articles/s41586-024-08224-z