Gliocidin is a nicotinamide-mimetic prodrug that targets glioblastoma

• 成果类型: Article
• 署名作者: 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.
• 署名单位: Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Rockefeller University; Rockefeller University; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; National Institutes of Health (NIH) - USA; Cornell University; Weill Cornell Medicine; Memorial Sloan Kettering Cancer Center; City of Hope; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5757
• DOI: 10.1038/s41586-024-08224-z
• 发表日期: 2024-12-12
• 页码: 466-+
• 关键词: cryo-em; dehydrogenase; mechanism; metabolism; DESIGN; nad(+)

摘要

Glioblastoma is incurable and in urgent need of improved therapeutics(1). 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 death(2). 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(+) pocket(3). 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.