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Gliocidin is a nicotinamide-mimetic prodrug that targets glioblastoma
- Source :
- Nature; December 2024, Vol. 636 Issue: 8042 p466-473, 8p
- Publication Year :
- 2024
-
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 Nmnat1expression, 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.
Details
- Language :
- English
- ISSN :
- 00280836 and 14764687
- Volume :
- 636
- Issue :
- 8042
- Database :
- Supplemental Index
- Journal :
- Nature
- Publication Type :
- Periodical
- Accession number :
- ejs68062568
- Full Text :
- https://doi.org/10.1038/s41586-024-08224-z