2024-03-28T11:29:28Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/2097452022-11-07T11:01:46Zcom_10261_81com_10261_5col_10261_334
http://hdl.handle.net/10261/209745
10.1016/j.biopha.2019.109601
390390
Pharmacology and preclinical validation of a novel anticancer compound targeting PEPCK-M
2020
artículo
Aragó, M.
Moreno-Felici, J.
Abás, S.
Rodríguez-Arévalo, S.
Hyroššová, P.
Figueras, A.
Viñals, F.
Pérez, B.
Loza, María Isabel
Brea, J.
Latorre, P.
Carrodeguas, José A.
García-Rovés, Pablo M.
Galdeano, Carles
Ginex, Tiziana
rp12434
Luque, F. Javier
Escolano, Carmen
Perales, J.C
PCK-M
Xanthine derivatives
PEPCK inhibitors
Cancer metabolism
Xenograft
Gluconeogenesis
Breast carcinoma
Colon carcinoma
Preclinical
Mitochondrial physiology
CETSA
Insulin secretion
2020
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.
Biomedicine and Pharmacotherapy 121