000130446 001__ 130446
000130446 005__ 20240125162930.0
000130446 0247_ $$2doi$$a10.1016/j.biopha.2019.109601
000130446 0248_ $$2sideral$$a115775
000130446 037__ $$aART-2020-115775
000130446 041__ $$aeng
000130446 100__ $$aAragó, M.
000130446 245__ $$aPharmacology and preclinical validation of a novel anticancer compound targeting PEPCK-M
000130446 260__ $$c2020
000130446 5060_ $$aAccess copy available to the general public$$fUnrestricted
000130446 5203_ $$aBackground: 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.
000130446 536__ $$9info:eu-repo/grantAgreement/ES/MINECO/BFU2015-66030-R$$9info:eu-repo/grantAgreement/ES/MINECO/SAF2017-85869-R
000130446 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc-nd$$uhttp://creativecommons.org/licenses/by-nc-nd/3.0/es/
000130446 590__ $$a6.529$$b2020
000130446 591__ $$aPHARMACOLOGY & PHARMACY$$b25 / 275 = 0.091$$c2020$$dQ1$$eT1
000130446 591__ $$aMEDICINE, RESEARCH & EXPERIMENTAL$$b27 / 140 = 0.193$$c2020$$dQ1$$eT1
000130446 592__ $$a1.323$$b2020
000130446 593__ $$aPharmacology$$c2020$$dQ1
000130446 593__ $$aMedicine (miscellaneous)$$c2020$$dQ1
000130446 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000130446 700__ $$aMoreno-Felici, J.
000130446 700__ $$aAbás, S.
000130446 700__ $$aRodríguez-Arévalo, S.
000130446 700__ $$aHyroššová, P.
000130446 700__ $$aFigueras, A.
000130446 700__ $$aViñals, F.
000130446 700__ $$aPérez, B.
000130446 700__ $$aLoza, M.I.
000130446 700__ $$aBrea, J.
000130446 700__ $$0(orcid)0000-0002-6794-3535$$aLatorre, Pedro
000130446 700__ $$0(orcid)0000-0003-0062-1029$$aCarrodeguas, José A.$$uUniversidad de Zaragoza
000130446 700__ $$aGarcía-Rovés, P.M.
000130446 700__ $$aGaldeano, C.
000130446 700__ $$aGinex, T.
000130446 700__ $$aLuque, F.J.
000130446 700__ $$aEscolano, C.
000130446 700__ $$aPerales, J.C.
000130446 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000130446 773__ $$g121 (2020), 109601 [10 pp.]$$pBiomed. pharmacother.$$tBIOMEDICINE & PHARMACOTHERAPY$$x0753-3322
000130446 8564_ $$s2358679$$uhttps://zaguan.unizar.es/record/130446/files/texto_completo.pdf$$yVersión publicada
000130446 8564_ $$s2481689$$uhttps://zaguan.unizar.es/record/130446/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000130446 909CO $$ooai:zaguan.unizar.es:130446$$particulos$$pdriver
000130446 951__ $$a2024-01-25-15:11:15
000130446 980__ $$aARTICLE