Gliocidin is a nicotinamide-mimetic prodrug that targets glioblastoma

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. Brink, Sean F. Brady, S. Kyun Lim and Luis F. Parada ()
Additional contact information
Yu-Jung Chen: Memorial Sloan Kettering Cancer Center
Swathi V. Iyer: Memorial Sloan Kettering Cancer Center
David Chun-Cheng Hsieh: The Rockefeller University
Buren Li: Memorial Sloan Kettering Cancer Center
Harold K. Elias: Memorial Sloan Kettering Cancer Center
Tao Wang: Memorial Sloan Kettering Cancer Center
Jing Li: Memorial Sloan Kettering Cancer Center
Mungunsarnai Ganbold: Memorial Sloan Kettering Cancer Center
Michelle C. Lien: Memorial Sloan Kettering Cancer Center
Yu-Chun Peng: Memorial Sloan Kettering Cancer Center
Xuanhua P. Xie: Memorial Sloan Kettering Cancer Center
Chenura D. Jayewickreme: Memorial Sloan Kettering Cancer Center
Marcel R. M. Brink: City of Hope
Sean F. Brady: The Rockefeller University
S. Kyun Lim: KOBIOLABS, Inc.
Luis F. Parada: Memorial Sloan Kettering Cancer Center

Nature, 2024, vol. 636, issue 8042, 466-473

Abstract: 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.

Date: 2024
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-024-08224-z Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:636:y:2024:i:8042:d:10.1038_s41586-024-08224-z

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-024-08224-z

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().