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.

胶质母细胞瘤无法治愈，迫切需要改进的治疗方法¹。在这里，我们鉴定了一种小化合物，即胶质灭虫素，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一磷酸脱氢酶 2 （IMPDH2） 靶向胶质母细胞瘤中的从头嘌呤合成脆弱性。IMPDH2 阻断可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²。Gliocidin 是一种前药，通过 NAD⁺ 挽救途径的烟酰胺核苷酸腺苷转移酶 1 （NMNAT1） 合成其杀肿瘤代谢物 gliocidin-腺嘌呤二核苷酸 （GAD）。GAD 与 IMPDH2 的冷冻电子显微镜结构证明了其进入、变形和阻断 NAD⁺ 口袋³。在体内，gliocidin 可穿透血脑屏障并延长原位胶质母细胞瘤小鼠的生存期。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模型中引起协同肿瘤细胞杀伤和额外的生存获益。这项研究揭示了胶质灭绝素作为一种前药，有可能提高胶质母细胞瘤患者的生存率。