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Title

Pharmacology and preclinical validation of a novel anticancer compound targeting PEPCK-M

AuthorsAragó, M.; Moreno-Felici, J.; Abás, S.; Rodríguez-Arévalo, S.; Hyroššová, P.; Figueras, A.; Viñals, F.; Pérez, B.; Loza, M.I.; Brea, J.; Latorre, P.; Carrodeguas, J.A.; García-Rovés, P.M.; Galdeano, C.; Ginex, T.; Luque, F.J.; Escolano, C.; Perales, J.C
KeywordsPCK-M
Xanthine derivatives
PEPCK inhibitors
Cancer metabolism
Xenograft
Gluconeogenesis
Breast carcinoma
Colon carcinoma
Preclinical
Mitochondrial physiology
CETSA,
Insulin secretion
Issue Date2020
CitationBiomedicine and Pharmacotherapy 121 (2020)
AbstractBackground: Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the decarboxylation of oxaloacetate to phosphoenolpyruvate. The mitochondrial isozyme, PEPCK-M is highly expressed in cancer cells, where it plays a role in nutrient stress response. To date, pharmacological strategies to target this pathway have not been pursued. Methods: A compound embodying a 3-alkyl-1,8-dibenzylxanthine nucleus (iPEPCK-2), was synthesized and successfully probed in silico on a PEPCK-M structural model. Potency and target engagement in vitro and in vivo were evaluated by kinetic and cellular thermal shift assays (CETSA). The compound and its target were validated in tumor growth models in vitro and in murine xenografts. Results: Cross-inhibitory capacity and increased potency as compared to 3-MPA were confirmed in vitro and in vivo. Treatment with iPEPCK-2 inhibited cell growth and survival, especially in poor-nutrient environment, consistent with an impact on colony formation in soft agar. Finally, daily administration of the PEPCK-M inhibitor successfully inhibited tumor growth in two murine xenograft models as compared to vehicle, without weight loss, or any sign of apparent toxicity. Conclusion: We conclude that iPEPCK-2 is a compelling anticancer drug targeting PEPCK-M, a hallmark gene product involved in metabolic adaptations of the tumor.
Publisher version (URL)http://dx.doi.org/10.1016/j.biopha.2019.109601
URIhttp://hdl.handle.net/10261/209745
Identifiersdoi: 10.1016/j.biopha.2019.109601
issn: 0753-3322
issn: 1950-6007
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