Gliocidin is a nicotinamide-mimetic prodrug that targets glioblastoma.

in Nature by Yu-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

TLDR

  • Gliocidin, a small compound, selectively kills glioblastoma cells by targeting a de novo purine synthesis vulnerability through indirect inhibition of IMPDH2.
  • Gliocidin's activity is selective for glioblastoma cells, sparing non-tumor replicative cells, and it extends the survival of mice with orthotopic glioblastoma.

Abstract

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 NADsalvage pathway. The cryo-electron microscopy structure of GAD together with IMPDH2 demonstrates its entry, deformation and blockade of the NADpocket. 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.

Overview

  • The study identifies a small compound, gliocidin, that selectively kills glioblastoma cells while sparing non-tumor replicative cells.
  • Gliocidin's activity targets a de novo purine synthesis vulnerability in glioblastoma cells through indirect inhibition of inosine monophosphate dehydrogenase 2 (IMPDH2).
  • The study aims to explore the potential of gliocidin as a prodrug to improve the survival of patients with glioblastoma.

Comparative Analysis & Findings

  • Gliocidin kills glioblastoma cells through its metabolite, gliocidin-adenine dinucleotide (GAD), which indirectly inhibits IMPDH2, leading to nucleotide imbalance, replication stress, and tumour cell death.
  • Gliocidin's activity is selective for glioblastoma cells, sparing non-tumor replicative cells.
  • In vivo studies demonstrate that gliocidin penetrates the blood-brain barrier and extends the survival of mice with orthotopic glioblastoma.

Implications and Future Directions

  • Gliocidin has the potential to improve the survival of patients with glioblastoma, offering a new therapeutic strategy for this incurable disease.
  • The synergy observed when combining gliocidin with temozolomide suggests a potential treatment approach for glioblastoma patients.
  • Future studies should explore the optimal dosing and administration schedule for gliocidin, as well as its combination with other therapies, to optimize its therapeutic potential.
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