Development of an efficient NUPR1 inhibitor with anticancer activity.

Autor: Liu X; Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR7258, Aix Marseille Université and Institut Paoli Calmettes, Parc Scientifique etTechnologique de Luminy, Equipe labéliséeLigue Nationale contre le cancer, 163 Avenue de Luminy, 13288, Marseille, France., Jimenez-Alesanco A; Instituto de Biocomputación y Física de Sistemas Complejos (BIFI), 50018, Zaragoza, Spain., Li Z; Chongqing Key Lab oratory of Natural Product Synthesis and Drug Research, School ofPharmaceutical Sciences, Chongqing University, No.55 Daxuecheng South Road, Chongqing, 401331, People's Republic of China., Rizzuti B; Instituto de Biocomputación y Física de Sistemas Complejos (BIFI), 50018, Zaragoza, Spain.; CNR NANOTEC, SS Rende (CS), Department of Physics, University of Calabria, Via P.Bucci, Cubo 31 C, 87036, Rende, Italy., Neira JL; Instituto de Biocomputación y Física de Sistemas Complejos (BIFI), 50018, Zaragoza, Spain.; IDIBE, Universidad Miguel Hernández, Edificio Torregaitán, Avda. del Ferrocarril s/n, 03202, Elche, Alicante, Spain., Estaras M; Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR7258, Aix Marseille Université and Institut Paoli Calmettes, Parc Scientifique etTechnologique de Luminy, Equipe labéliséeLigue Nationale contre le cancer, 163 Avenue de Luminy, 13288, Marseille, France., Peng L; Aix Marseille Université, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille, UMR7325, Parc Scientifique et Technologique de Luminy, Equipe labélisée Ligue Nationale contre le cancer, 163 Avenue de Luminy, 13288, Marseille, France., Chuluyan E; Center for Pharmacological and Botanical Studies, Faculty of Medicine, National Council for Scientific and Technical Research, Buenos Aires University, C1121ABG, Buenos Aires, Argentina.; Department of Microbiology, Parasitology and Immunology, Faculty of Medicine, Buenos Aires University, C1121ABG, Buenos Aires, Argentina., Garona J; Hospital de Alta Complejidad El Cruce, Florencio Varela, Buenos Aires, Argentina.; University Arturo Jauretche, Florencio Varela, Buenos Aires, Argentina., Gottardo F; Hospital de Alta Complejidad El Cruce, Florencio Varela, Buenos Aires, Argentina.; University Arturo Jauretche, Florencio Varela, Buenos Aires, Argentina., Velazquez-Campoy A; Instituto de Biocomputación y Física de Sistemas Complejos (BIFI), 50018, Zaragoza, Spain.; Aragon Institute for Health Research (IIS Aragon), Zaragoza, Spain.; Centro de Investigación Biomédica en Red en el Área Temática de Enfe rmedadesHepáticas y Digestivas (CIBERehd), Madrid, Spain.; Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain., Xia Y; Chongqing Key Lab oratory of Natural Product Synthesis and Drug Research, School ofPharmaceutical Sciences, Chongqing University, No.55 Daxuecheng South Road, Chongqing, 401331, People's Republic of China., Abian O; Instituto de Biocomputación y Física de Sistemas Complejos (BIFI), 50018, Zaragoza, Spain.; Aragon Institute for Health Research (IIS Aragon), Zaragoza, Spain.; Centro de Investigación Biomédica en Red en el Área Temática de Enfe rmedadesHepáticas y Digestivas (CIBERehd), Madrid, Spain.; Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain., Santofimia-Castaño P; Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR7258, Aix Marseille Université and Institut Paoli Calmettes, Parc Scientifique etTechnologique de Luminy, Equipe labéliséeLigue Nationale contre le cancer, 163 Avenue de Luminy, 13288, Marseille, France. patricia.santofimia@inserm.fr., Iovanna J; Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR7258, Aix Marseille Université and Institut Paoli Calmettes, Parc Scientifique etTechnologique de Luminy, Equipe labéliséeLigue Nationale contre le cancer, 163 Avenue de Luminy, 13288, Marseille, France. juan.iovanna@inserm.fr.; Hospital de Alta Complejidad El Cruce, Florencio Varela, Buenos Aires, Argentina. juan.iovanna@inserm.fr.; University Arturo Jauretche, Florencio Varela, Buenos Aires, Argentina. juan.iovanna@inserm.fr.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Nov 27; Vol. 14 (1), pp. 29515. Date of Electronic Publication: 2024 Nov 27.
DOI: 10.1038/s41598-024-79340-z
Abstrakt: Pancreatic 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.
Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval and consent to participate: All animal care and experimental procedures were performed in agreement with the Animal Ethics Committee of Marseille number 14 (C2EA-14). Approval Number: 202011181636926.
(© 2024. The Author(s).)
Databáze: MEDLINE
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