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Pro-905, a Novel Purine Antimetabolite, Combines with Glutamine Amidotransferase Inhibition to Suppress Growth of Malignant Peripheral Nerve Sheath Tumor
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SYSNO ASEP 0576214 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Pro-905, a Novel Purine Antimetabolite, Combines with Glutamine Amidotransferase Inhibition to Suppress Growth of Malignant Peripheral Nerve Sheath Tumor Author(s) Lemberg, K. M. (US)
Ali, E. S. (US)
Krečmerová, Marcela (UOCHB-X) RID, ORCID
Aguilar, J. M. H. (US)
Alt, J. (US)
Peters, D. E. (US)
Zhao, L. (US)
Wu, Y. (FR)
Nuha, N. (US)
Asara, J. M. (US)
Staedtke, V. (US)
Pratilas, C. A. (US)
Majer, Pavel (UOCHB-X)
Rais, R. (US)
Ben-Sahra, I. (US)
Slusher, B. S. (US)Source Title Molecular Cancer Therapeutics. - : American Association for Cancer Research - ISSN 1535-7163
Roč. 22, č. 12 (2023), s. 1390-1403Number of pages 14 s. Language eng - English Country US - United States Keywords loading 6-mercaptopurine therapies ; standard dose 6-mercaptopurine ; combination 6-mercaptopurine OECD category Medicinal chemistry R&D Projects LM2023053 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support UOCHB-X - RVO:61388963 UT WOS 001154413900008 EID SCOPUS 85178651092 DOI 10.1158/1535-7163.MCT-23-0258 Annotation 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 well-tolerated 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. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Year of Publishing 2024 Electronic address https://doi.org/10.1158/1535-7163.MCT-23-0258
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