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https://hdl.handle.net/2445/174403
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 Farmacologia Càncer de mama Càncer colorectal Adjuvant treatment of cancer Pharmacology 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. |
Note: | Reproducció del document publicat a: https://doi.org/10.1016/j.biopha.2019.109601 |
It is part of: | Biomedicine & Pharmacotherapy, 2020, vol. 121, num. 109601 |
URI: | https://hdl.handle.net/2445/174403 |
Related resource: | https://doi.org/10.1016/j.biopha.2019.109601 |
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 de Química Teòrica i Computacional (IQTCUB)) Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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