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Title: Pharmacology and preclinical validation of a novel anticancer compound targeting PEPCK-M
Author: Aragó, Marc
Moreno Felici, Juan
Abás Prades, Sònia
Rodríguez Arévalo, Sergio
Hyrossová, Petra
Figueras, Agnes
Viñals Canals, Francesc
Pérez, Belén
Loza, María Isabel
Brea, José
Latorre, Pedro
Carrodeguas, Jose A.
García-Roves, Pablo M. (Pablo Miguel)
Galdeano, Carlos
Ginex, Tiziana
Luque Garriga, F. Xavier
Escolano Mirón, Carmen
Perales Losa, Carlos
Keywords: Tractament adjuvant del càncer
Càncer de mama
Càncer colorectal
Adjuvant treatment of cancer
Breast cancer
Colorectal cancer
Issue Date: 2020
Publisher: Elsevier Masson SAS
Abstract: Background: 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.
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It is part of: Biomedicine & Pharmacotherapy, 2020, vol. 121, num. 109601
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ISSN: 0753-3322
Appears in Collections:Articles publicats en revistes (Institut de Biomedicina (IBUB))
Articles publicats en revistes (Farmàcia, Tecnologia Farmacèutica i Fisicoquímica)
Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)
Articles publicats en revistes (Ciències Fisiològiques)
Articles publicats en revistes (Nutrició, Ciències de l'Alimentació i Gastronomia)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (Institut de Química Teòrica i Computacional (IQTCUB))

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