RT Journal Article
T1 Pharmacology and preclinical validation of a novel anticancer compound targeting PEPCK-M
A1 Aragó, Marc
A1 Moreno-Felici, Juan
A1 Abás, Sonia
A1 Rodríguez-Arévalo, Sergio
A1 Hyroššová, Petra
A1 Figueras, Agnes
A1 Viñals, Francesc
A1 Pérez, Belén
A1 Latorre, Pedro
A1 Carrodeguas, Jose A.
A1 García-Rovés, Pablo M.
A1 Galdeano, Carlos
A1 Ginex, Tiziana
A1 Luque, Francisco J.
A1 Escolano, Carmen
A1 Perales, Jose C.
A1 Brea Floriani, José Manuel
A1 Loza García, María Isabel
K1 PEPCK-M
K1 Xanthine derivatives
K1 PEPCK inhibitors
K1 Cancer metabolism
K1 Xenograft
K1 Gluconeogenesis
K1 Breast carcinoma
K1 Colon carcinoma
K1 Preclinical
K1 Mitochondrial physiology
K1 CETSA
K1 Insulin secretion
AB BackgroundPhosphoenolpyruvate 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.MethodsA 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.ResultsCross-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.ConclusionWe conclude that iPEPCK-2 is a compelling anticancer drug targeting PEPCK-M, a hallmark gene product involved in metabolic adaptations of the tumor.
PB Elsevier
SN 0753-3322
YR 2020
FD 2020-01
LK https://hdl.handle.net/10347/44991
UL https://hdl.handle.net/10347/44991
LA eng
NO Marc Aragó, Juan Moreno-Felici, Sonia Abás, Sergio Rodríguez-Arévalo, Petra Hyroššová, Agnes Figueras, Francesc Viñals, Belén Pérez, Maria I. Loza, Jose Brea, Pedro Latorre, Jose A. Carrodeguas, Pablo M. García-Rovés, Carlos Galdeano, Tiziana Ginex, Francisco J. Luque, Carmen Escolano, Jose C. Perales, Pharmacology and preclinical validation of a novel anticancer compound targeting PEPCK-M, Biomedicine & Pharmacotherapy, Volume 121, 2020, 109601, ISSN 0753-3322, https://doi.org/10.1016/j.biopha.2019.109601.
DS Minerva
RD 3 may 2026