title: Identification of a Drug Targeting an Intrinsically Disordered Protein Involved in Pancreatic Adenocarcinoma.
abstract: Intrinsically disordered proteins (IDPs) are prevalent in eukaryotes, performing signaling and regulatory functions. Often associated with human diseases, they constitute drug-development targets. NUPR1 is a multifunctional IDP, over-expressed and involved in pancreatic ductal adenocarcinoma (PDAC) development. By screening 1120 FDA-approved compounds, fifteen candidates were selected, and their interactions with NUPR1 were characterized by experimental and simulation techniques. The protein remained disordered upon binding to all fifteen candidates. These compounds were tested in PDAC-derived cell-based assays, and all induced cell-growth arrest and senescence, reduced cell migration, and decreased chemoresistance, mimicking NUPR1-deficiency. The most effective compound completely arrested tumor development in vivo on xenografted PDAC-derived cells in mice. Besides reporting the discovery of a compound targeting an intact IDP and specifically active against PDAC, our study proves the possibility to target the 'fuzzy' interface of a protein that remains disordered upon binding to its natural biological partners or to selected drugs.
authors.affiliation: Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, Edificio Torregaitán, Avda. del Ferrocarril s/n, 03202 Elche, Alicante, Spain.|Instituto de Biocomputación y Física de Sistemas Complejos (BIFI), Unidad Asociada IQFR-CSIC-BIFI, Universidad de Zaragoza, Edificio I+D, Mariano Esquillor s/n, 50018 Zaragoza, Spain.
authors.forename: José L
authors.initials: JL
authors.lastname: Neira
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, 163 Avenue de Luminy, 13288, Marseille, France.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bintz
authors.affiliation: Instituto Aragonés de Ciencias de la Salud (IACS), Av. San Juan Bosco 13, 50009 Zaragoza, Spain.|Instituto de Investigaciones Sanitarias (IIS) Aragón, Av. San Juan Bosco, 13, 50009 Zaragoza, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Arruebo
authors.affiliation: CNR-NANOTEC, Licryl-UOS Cosenza and CEMIF.Cal, Department of Physics, University of Calabria, Via P. Bucci, Cubo 31 C, 87036 Arcavacata di Rende, Cosenza, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Rizzuti
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, 163 Avenue de Luminy, 13288, Marseille, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bonacci
authors.affiliation: Instituto de Biocomputación y Física de Sistemas Complejos (BIFI), Unidad Asociada IQFR-CSIC-BIFI, Universidad de Zaragoza, Edificio I+D, Mariano Esquillor s/n, 50018 Zaragoza, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Vega
authors.affiliation: Instituto de Investigaciones Sanitarias (IIS) Aragón, Av. San Juan Bosco, 13, 50009 Zaragoza, Spain.|Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain.|Servicio de Aparato Digestivo, Hospital Clínico Universitario "Lozano Blesa", Av. San Juan Bosco, 15, 50009 Zaragoza, Spain.|Department of Medicine, University of Zaragoza, Perdro Cerbuna 12, 50009 Zaragoza, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Lanas
authors.affiliation: Instituto de Biocomputación y Física de Sistemas Complejos (BIFI), Unidad Asociada IQFR-CSIC-BIFI, Universidad de Zaragoza, Edificio I+D, Mariano Esquillor s/n, 50018 Zaragoza, Spain.|Instituto de Investigaciones Sanitarias (IIS) Aragón, Av. San Juan Bosco, 13, 50009 Zaragoza, Spain.|Fundación ARAID, Diputación General de Aragón, C/María de Luna 11, Edificio CEEIARAGÓN, 50018 Zaragoza, Spain.
authors.forename: Adrián
authors.initials: A
authors.lastname: Velázquez-Campoy
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, 163 Avenue de Luminy, 13288, Marseille, France.
authors.forename: Juan L
authors.initials: JL
authors.lastname: Iovanna
authors.affiliation: Instituto de Biocomputación y Física de Sistemas Complejos (BIFI), Unidad Asociada IQFR-CSIC-BIFI, Universidad de Zaragoza, Edificio I+D, Mariano Esquillor s/n, 50018 Zaragoza, Spain.|Instituto Aragonés de Ciencias de la Salud (IACS), Av. San Juan Bosco 13, 50009 Zaragoza, Spain.|Instituto de Investigaciones Sanitarias (IIS) Aragón, Av. San Juan Bosco, 13, 50009 Zaragoza, Spain.|Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Abián
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D044584:Carcinoma, Ductal / Q000188:drug therapy / Q000378:metabolism*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D016922:Cellular Senescence; D055808:Drug Discovery; D019008:Drug Resistance, Neoplasm; D006801:Humans; D064267:Intrinsically Disordered Proteins / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011485:Protein Binding; D014268:Trifluoperazine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D064267:Intrinsically Disordered Proteins; D009363:Neoplasm Proteins; D014268:Trifluoperazine; C491643:NUPR1 protein, human; C032476:trifluoperazine dimaleate