Designing and repurposing drugs to target intrinsically disordered proteins for cancer treatment: using NUPR1 as a paradigm

Patricia Santofimia-Castaño; Bruno Rizzuti; Yi Xia; Olga Abian; Ling Peng; Adrián Velázquez-Campoy; Juan L Iovanna; José L Neira

doi:10.1080/23723556.2019.1612678

Designing and repurposing drugs to target intrinsically disordered proteins for cancer treatment: using NUPR1 as a paradigm

Mol Cell Oncol. 2019 May 16;6(5):e1612678. doi: 10.1080/23723556.2019.1612678. eCollection 2019.

Authors

Patricia Santofimia-Castaño¹, Bruno Rizzuti², Yi Xia³, Olga Abian^{4

5

6

7

8}, Ling Peng⁹, Adrián Velázquez-Campoy^{4

5

6

7

10}, Juan L Iovanna¹, José L Neira^{4

11}

Affiliations

¹ 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, Marseille, France.
² CNR-NANOTEC, Licryl-UOS Cosenza and CEMIF.Cal, Department of Physics, University of Calabria, Rende, Italy.
³ Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing, P. R. China.
⁴ Instituto de Biocomputación y Física de Sistemas Complejos (BIFI), Joint Units IQFR-CSIC-BIFI, and GBsC-CSIC-BIFI, Universidad de Zaragoza, Zaragoza, Spain.
⁵ Aragon Institute for Health Research (IIS Aragon), Zaragoza, Spain.
⁶ Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
⁷ Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.
⁸ Instituto Aragonés de Ciencias de la Salud (IACS), Zaragoza, Spain.
⁹ Aix-Marseille Université, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille, UMR 7325, «Equipe Labellisée Ligue Contre le Cancer», Parc Scientifique et Technologique de Luminy, Marseille, France.
¹⁰ Fundacion ARAID, Government of Aragon, Zaragoza, Spain.
¹¹ Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, Alicante, Spain.

Abstract

Intrinsically disordered proteins (IDPs) do not have a well-defined structure, but they have key biological tasks in cancer development. By using the disordered cancer-related protein NUPR1 as a proof-of-concept, we have developed a new multidisciplinary approach to tackle drug-design against IDPs, using it to repurpose drugs for treating pancreatic adenocarcinoma (PDAC).

Keywords: Drug design; NUPR1; intrinsically disordered protein; molecular dynamics; protein-protein interactions; spectroscopy.

Grants and funding

This work in the authors’ laboratories was supported by [La Ligue Contre le Cancer], INCa, [Canceropole PACA] and [INSERM] to JLI and LP; [Miguel Servet Program from Instituto de Salud Carlos III] under grant [CPII13/00017] to OA; Fondo de Investigaciones Sanitarias from Instituto de Salud Carlos III, and European Union (ERDF/ESF, 'Investing in your future') under grants [PI15/00663 and PI18/00349] to OA; Ministerio de Economía, Industria y Competitividad, Gobierno de España under grants [BFU2016-78232-P to AVC, CTQ2015-64445-R to JLN]; [Diputación General de Aragón] under grants [Protein Targets and Bioactive Compound Group to AVC, and Digestive Pathology Group to OA]; [Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas] (CIBERehd) to OA and AVC; [Programme XU GUANGQI] to YX and JLI; and [National Natural Science Foundation of China (81502920), the Fundamental Research Funds for the Central Universities] under grant [106112017CDJQJ468823] to YX. The Fundación Alfonso Martín-Escudero and Fondation de France supported to PSC.