2. Academic Validation
  3. Gliocidin is a nicotinamide-mimetic prodrug that targets glioblastoma

Gliocidin is a nicotinamide-mimetic prodrug that targets glioblastoma

  • Nature. 2024 Nov 20. doi: 10.1038/s41586-024-08224-z.
Yu-Jung Chen 1 2,  Swathi V Iyer # 2,  David Chun-Cheng Hsieh # 3 4,  Buren Li # 5,  Harold K Elias 6 7,  Tao Wang 2 8,  Jing Li 9,  Mungunsarnai Ganbold 2 9,  Michelle C Lien 9,  Yu-Chun Peng 9,  Xuanhua P Xie 2,  Chenura D Jayewickreme 2,  Marcel R M van den Brink 10,  Sean F Brady 4,  S Kyun Lim 11,  Luis F Parada 12 13 14 15
Affiliations

Affiliations

  • 1 Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 2 Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 3 Tri-Institutional PhD Program in Chemical Biology, The Rockefeller University, New York, NY, USA.
  • 4 Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, New York, NY, USA.
  • 5 Structure Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 6 Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 7 National Institutes of Health, Bethesda, MD, USA.
  • 8 Neuroscience Program, Weill Cornell Medicine Graduate School of Medical Sciences, New York, NY, USA.
  • 9 Brain Tumor Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 10 City of Hope, Los Angeles, CA, USA.
  • 11 KOBIOLABS, Inc., Seongnam-si, South Korea.
  • 12 Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. paradal@mskcc.org.
  • 13 Brain Tumor Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA. paradal@mskcc.org.
  • 14 Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. paradal@mskcc.org.
  • 15 Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. paradal@mskcc.org.
  • # Contributed equally.
PMID: 39567689 DOI: 10.1038/s41586-024-08224-z
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.

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