000147199 001__ 147199 000147199 005__ 20241212141913.0 000147199 0247_ $$2doi$$a10.1038/s41598-024-79340-z 000147199 0248_ $$2sideral$$a141041 000147199 037__ $$aART-2024-141041 000147199 041__ $$aeng 000147199 100__ $$aLiu, Xi 000147199 245__ $$aDevelopment of an efficient NUPR1 inhibitor with anticancer activity 000147199 260__ $$c2024 000147199 5060_ $$aAccess copy available to the general public$$fUnrestricted 000147199 5203_ $$aPancreatic cancer is highly lethal and has limited treatment options available. Our team had previously developed ZZW-115, a promising drug candidate that targets the nuclear protein 1 (NUPR1), which is involved in pancreatic cancer development and progression. However, clinical translation of ZZW-115 was hindered due to potential cardiotoxicity caused by its interaction with the human Ether-à-go-go-Related Gene (hERG) potassium channel. To address this, we have performed a high-throughput screening of 10,000 compounds from the HitFinder Chemical Library, and identified AJO14 as a lead compound that binds to NUPR1, without having favorable affinity towards hERG. AJO14 induced cell death through apoptosis, necroptosis, and parthanatos (induced by the poly-ADP ribose polymerase (PARP) overactivation), driven by mitochondrial catastrophe and decreased ATP production. This process seemed to be mediated by the hyperPARylation (an excessive modification of proteins by PARP, leading to cellular dysfunction), as it could be reversed by Olaparib, a PARP inhibitor. In xenografted mice, AJO14 demonstrated a dose-dependent tumor reduction activity. Furthermore, we attempted to improve the anti-cancer properties of AJO14 by molecular modification of the lead compound. Among the 51 candidates obtained and tested, 8 compounds exhibited a significant increase in efficacy and have been retained for further studies, especially LZX-2-73. These AJO14-derived compounds offer potent NUPR1 inhibition for pancreatic cancer treatment, without cardiotoxicity concerns. 000147199 536__ $$9info:eu-repo/grantAgreement/ES/DGA/B25-23R$$9info:eu-repo/grantAgreement/ES/DGA/E45-23R$$9info:eu-repo/grantAgreement/ES/ISCIII-ERDF-ESF/PI21-00394$$9info:eu-repo/grantAgreement/ES/MCIU-AEI-FEDER/BFU2016-78232-P$$9info:eu-repo/grantAgreement/ES/MICINN/AEI/PID2021-127296OB-I00$$9info:eu-repo/grantAgreement/ES/MICINN-AEI/PRTR-C17.I1 000147199 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc-nd$$uhttp://creativecommons.org/licenses/by-nc-nd/3.0/es/ 000147199 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion 000147199 700__ $$0(orcid)0000-0003-4726-7821$$aJimenez-Alesanco, Ana$$uUniversidad de Zaragoza 000147199 700__ $$aLi, Zexian 000147199 700__ $$aRizzuti, Bruno 000147199 700__ $$aNeira, José L. 000147199 700__ $$aEstaras, Matías 000147199 700__ $$aPeng, Ling 000147199 700__ $$aChuluyan, Eduardo 000147199 700__ $$aGarona, Juan 000147199 700__ $$aGottardo, Florencia 000147199 700__ $$0(orcid)0000-0001-5702-4538$$aVelazquez-Campoy, Adrián$$uUniversidad de Zaragoza 000147199 700__ $$aXia, Yi 000147199 700__ $$0(orcid)0000-0001-5664-1729$$aAbian, Olga$$uUniversidad de Zaragoza 000147199 700__ $$aSantofimia-Castaño, Patricia 000147199 700__ $$aIovanna, Juan 000147199 7102_ $$11011$$2566$$aUniversidad de Zaragoza$$bDpto. Microb.Ped.Radio.Sal.Pú.$$cÁrea Inmunología 000147199 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole. 000147199 773__ $$g14, 1 (2024), 29515 [20 pp.]$$pSci. rep. (Nat. Publ. Group)$$tScientific reports (Nature Publishing Group)$$x2045-2322 000147199 8564_ $$s10504095$$uhttps://zaguan.unizar.es/record/147199/files/texto_completo.pdf$$yVersión publicada 000147199 8564_ $$s2467320$$uhttps://zaguan.unizar.es/record/147199/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada 000147199 909CO $$ooai:zaguan.unizar.es:147199$$particulos$$pdriver 000147199 951__ $$a2024-12-12-12:44:51 000147199 980__ $$aARTICLE