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Gliocidin is a nicotinamide-mimetic prodrug that targets glioblastoma
Yu-Jung Chen1,2, Swathi V Iyer2, David Chun-Cheng Hsieh3,4
1Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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.
Insights
A new compound, gliocidin, effectively kills glioblastoma cells by targeting purine synthesis. This prodrug shows promise for improving glioblastoma patient survival and penetrates the blood-brain barrier.
Area of Science:
- Oncology
- Biochemistry
- Pharmacology
Background:
- Glioblastoma is an aggressive brain cancer with limited treatment options.
- There is an urgent need for novel therapeutics to improve patient outcomes.
Purpose of the Study:
- To identify and characterize a novel small compound, gliocidin, with potent anti-glioblastoma activity.
- To elucidate the mechanism of action and therapeutic potential of gliocidin.
Main Methods:
- Screening of small compounds for glioblastoma cell killing activity.
- Biochemical assays to determine the target of gliocidin, inosine monophosphate dehydrogenase 2 (IMPDH2).
- Cryo-electron microscopy to visualize the interaction of gliocidin's metabolite with IMPDH2.
- In vivo studies using orthotopic glioblastoma mouse models to assess efficacy and blood-brain barrier penetration.
Main Results:
- Gliocidin selectively kills glioblastoma cells by inhibiting de novo purine synthesis via IMPDH2.
- Gliocidin is a prodrug activated to gliocidin-adenine dinucleotide (GAD), which blocks the NAD+ pocket of IMPDH2.
- Gliocidin demonstrated efficacy in vivo, crossing the blood-brain barrier and extending survival in glioblastoma models.
- Combination therapy with temozolomide showed synergistic effects, enhancing tumor cell killing and survival benefit.
Conclusions:
- Gliocidin is a promising prodrug targeting a specific vulnerability in glioblastoma.
- Its ability to penetrate the blood-brain barrier and synergistic effect with temozolomide warrant further investigation for clinical application.
- Gliocidin represents a potential new therapeutic strategy for glioblastoma patients.
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