1. Identification of a Drug Targeting an Intrinsically Disordered Protein Involved in Pancreatic Adenocarcinoma
- Author
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Angel Lanas, Juan L. Iovanna, Thomas Bonacci, Maria Arruebo, José L. Neira, Olga Abian, Sonia Vega, Adrián Velázquez-Campoy, Jennifer Bintz, Bruno Rizzuti, Ministerio de Economía y Competitividad (España), Instituto de Biología Molecular y Celular [Alicante, Spain], Universidad Miguel Hernández [Elche] (UMH), Unidad Asociada IQFR-CSIC-BIFI [Zaragoza, Spain], University of Zaragoza - Universidad de Zaragoza [Zaragoza]-Instituto de Biocomputación y Física de Sistemas Complejos - BIFI [Zaragoza, Spain], Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Instituto Aragonés de Ciencias de la Salud [Zaragoza] (IACS), Instituto de Investigaciones Sanitarias - IIS [Zaragoza, Spain], CNR-NANOTEC, Licryl-UOS Cosenza & CEMIF.Cal [Cosenza, Italy] (Department of Physics), University of Calabria [Cosenza, Italy], Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Liver Unit, Clínica Universitaria, CIBER-EHD, Servicio de Aparato Digestivo [Zaragoza, Spain], Hospital Clínico Universitario 'Lozano Blesa' [Zaragoza, Spain], Department of Medicine [Zaragoza, Spain], University of Zaragoza - Universidad de Zaragoza [Zaragoza], Fundación ARAID [Zaragoza, Spain], Diputación General de Aragón [Zaragoza, Spain], This work was supported by La Ligue Contre le Cancer, INCa, Canceropole PACA, DGOS (labellisation SIRIC) and INSERM to JLI, Miguel Servet Program from Instituto de Salud Carlos III (CPII13/00017 to OA), Fondo de Investigaciones Sanitarias (PI10/00186 and PI15/00663 to OA, PI11/02578 to AL), Spanish Ministry of Economy and Competitiveness (BFU2013-47064-P to AVC, CTQ2015-64445-R to JLN), Diputación General de Aragón (Protein Targets Group B89 to AVC, and Digestive Pathology Group B01 to OA, MA and AL), Generalitat Valenciana (Prometeo 018/2013 to JLN), and Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd)., Università della Calabria [Arcavacata di Rende] (Unical), Fundación Agencia Aragonesa para la Investigación y el Desarrollo (ARAID), and MITOYAN, Louciné
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0301 basic medicine ,[SDV]Life Sciences [q-bio] ,Cell ,Mice, Nude ,Antineoplastic Agents ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Plasma protein binding ,Intrinsically disordered proteins ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Cell Movement ,Cell Line, Tumor ,Drug Discovery ,medicine ,Basic Helix-Loop-Helix Transcription Factors ,Animals ,Humans ,Molecular Targeted Therapy ,Cellular Senescence ,Cell Proliferation ,Multidisciplinary ,Chemistry ,Drug discovery ,Cell growth ,Cell Cycle ,Cell migration ,Cell cycle ,Xenograft Model Antitumor Assays ,Trifluoperazine ,3. Good health ,Neoplasm Proteins ,[SDV] Life Sciences [q-bio] ,Carcinoma, Ductal ,Intrinsically Disordered Proteins ,Pancreatic Neoplasms ,030104 developmental biology ,medicine.anatomical_structure ,Targeted drug delivery ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,Protein Binding - 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.
- Published
- 2017
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