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TitleGliocidin is a nicotinamide-mimetic prodrug that targets glioblastoma.
Journal, issue, pagesNature, Vol. 636, Issue 8042, Page 466-473, Year 2024
Publish dateNov 20, 2024
AuthorsYu-Jung Chen / Swathi V Iyer / David Chun-Cheng Hsieh / Buren Li / Harold K Elias / Tao Wang / Jing Li / Mungunsarnai Ganbold / Michelle C Lien / Yu-Chun Peng / Xuanhua P Xie / Chenura D Jayewickreme / Marcel R M van den Brink / Sean F Brady / S Kyun Lim / Luis F Parada /
PubMed AbstractGlioblastoma is incurable and in urgent need of improved therapeutics. Here we identify a small compound, gliocidin, that kills glioblastoma cells while sparing non-tumour replicative cells. ...Glioblastoma is incurable and in urgent need of improved therapeutics. 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. 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. 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.
External linksNature / PubMed:39567689 / PubMed Central
MethodsEM (single particle)
Resolution1.82 Å
Structure data

47016

9dmu

EMDB-47016, PDB-9dmu:
Cryo-EM structure of IMPDH2 bound to IMP and GAD
Method: EM (single particle) / Resolution: 1.82 Å

Chemicals

ChemComp-IMP:
INOSINIC ACID

PDB-1a7t:
METALLO-BETA-LACTAMASE WITH MES

ChemComp-K:
Unknown entry

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsOXIDOREDUCTASE / dehydrogenase / substrate / inhibitor

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