Pro-905, a Novel Purine Antimetabolite, Combines with Glutamine Amidotransferase Inhibition to Suppress Growth of Malignant Peripheral Nerve Sheath Tumor

Kathryn M. Lemberg, Eunus S. Ali, Marcela Krecmerova, Joanna Marie H. Aguilar, Jesse Alt, Diane E. Peters, Liang Zhao, Ying Wu, Naziba Nuha, John M. Asara, Verena Staedtke, Christine A. Pratilas, Pavel Majer, Rana Rais, Issam Ben-Sahra, Barbara S. Slusher

Research output: Contribution to journalArticlepeer-review

Abstract

Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive soft-tissue sarcomas that arise from neural tissues and carry a poor prognosis. Previously, we found that the glutamine amidotransferase inhibitor JHU395 partially impeded tumor growth in preclinical models of MPNST. JHU395 inhibits de novo purine synthesis in human MPNST cells and murine tumors with partial decreases in purine monophosphates. On the basis of prior studies showing enhanced efficacy when glutamine amidotransferase inhibition was combined with the antimetabolite 6-mercaptopurine (6-MP), we hypothesized that such a combination would be efficacious in MPNST. Given the known toxicity associated with 6-MP, we set out to develop a more efficient and welltolerated drug that targets the purine salvage pathway. Here, we report the discovery of Pro-905, a phosphoramidate protide that delivered the active nucleotide antimetabolite thioguanosine monophosphate (TGMP) to tumors over 2.5 times better than equimolar 6-MP. Pro-905 effectively prevented the incorporation of purine salvage substrates into nucleic acids and inhibited colony formation of human MPNST cells in a dose-dependent manner. In addition, Pro-905 inhibited MPNST growth and was well-tolerated in both human patient-derived xenograft (PDX) and murine flank MPNST models. When combined with JHU395, Pro-905 enhanced the colony formation inhibitory potency of JHU395 in human MPNST cells and augmented the antitumor efficacy of JHU395 in mice. In summary, the dual inhibition of the de novo and purine salvage pathways in preclinical models may safely be used to enhance therapeutic efficacy against MPNST.

Original languageEnglish
Pages (from-to)1390-1403
Number of pages14
JournalMolecular Cancer Therapeutics
Volume22
Issue number12
DOIs
StatePublished - 2023

Bibliographical note

Publisher Copyright:
© 2023 The Authors.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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