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

Biomedicine & Pharmacotherapy

卷:121

Belén Pérez¹  Carmen Escolano²  Francisco J. Luque²  Maria I. Loza³  Tiziana Ginex⁴  Francesc Viñals⁵  Petra Hyroššová⁵  Carlos Galdeano⁵  Marc Aragó⁵  Juan Moreno-Felici⁵  Jose Brea⁶  Pedro Latorre⁶  Jose A. Carrodeguas⁷  Pablo M. García-Rovés⁷  Jose C. Perales⁸  Sergio Rodríguez-Arévalo⁸  Sonia Abás⁸  Agnes Figueras⁹ 

[1] Programs of Molecular Mechanisms and Experimental Therapeutics in Oncology (ONCOBell), and Cancer Therapeutics Resistance (ProCURE), Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Spain;

[2] Department of Nutrition, Food Sciences and Gastronomy, School of Pharmacy and Food Sciences, Institute of Biomedicine (IBUB), and Institute of Theoretical and Computational Chemistry (IQTCUB), University of Barcelona, Santa Coloma de Gramanet, Spain;

[3] Department of Pharmacology, Therapeutic and Toxicology, Autonomous University of Barcelona, Bellaterra, Spain;

[4] Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, School of Pharmacy, and Institute of Biomedicine (IBUB), University of Barcelona, Barcelona, Spain;

[5] Department of Physiological Sciences, School of Medicine, University of Barcelona, L’Hospitalet del Llobregat, Spain;

[6] Innopharma Screening Platform, BioFarma Research Group, Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidad de Santiago de Compostela, Santiago de Compostela, Spain;

[7] Instituto de Biocomputación y Física de Sistemas Complejos (BIFI), BIFI-IQFR (CSIC), Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza, Spain;

[8] Laboratory of Medicinal Chemistry (Associated Unit to CSIC), Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona, Barcelona, Spain;

关键词: PEPCK-M;    Xanthine derivatives;    PEPCK inhibitors;    Cancer metabolism;    Xenograft;    Gluconeogenesis;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown