2. Academic Validation
  3. Ligand-based design identifies a potent NUPR1 inhibitor exerting anticancer activity via necroptosis

Ligand-based design identifies a potent NUPR1 inhibitor exerting anticancer activity via necroptosis

  • J Clin Invest. 2019 Mar 28;129(6):2500-2513. doi: 10.1172/JCI127223.
Patricia Santofimia-Castaño 1,  Yi Xia 2,  Wenjun Lan 1 3,  Zhengwei Zhou 2,  Can Huang 1,  Ling Peng 3,  Philippe Soubeyran 1,  Adrián Velázquez-Campoy 4 5,  Olga Abián 4 6,  Bruno Rizzuti 7,  José L Neira 8,  Juan Iovanna 1
Affiliations

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 Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing, China.
  • 3 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.
  • 4 Instituto de Biocomputación y Física de Sistemas Complejos, Joint Units IQFR-CSIC-BIFI, and GBsC-CSIC-BIFI, Universidad de Zaragoza, Spain; Instituto Aragonés de Ciencias de la Salud (IACS), Zaragoza, Spain; Aragon Institute for Health Research (IIS Aragon), Zaragoza, Spain; Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.
  • 5 Fundacion ARAID, Government of Aragon, Zaragoza, Spain.
  • 6 Instituto Aragonés de Ciencias de la Salud (IACS), Zaragoza, Spain.
  • 7 CNR-NANOTEC, Licryl-UOS Cosenza and CEMIF.Cal, Department of Physics, University of Calabria, Cosenza, Italy.
  • 8 Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, Edificio Torregaitán, Alicante, Spain.
PMID: 30920390 DOI: 10.1172/JCI127223
Abstract

Intrinsically disordered proteins (IDPs) are emerging as attractive drug targets by virtue of their prevalence in various diseases including Cancer. Drug development targeting IDPs is challenging because they have dynamical structure features and conventional drug design is not applicable. NUPR1 is an IDP playing an important role in pancreatic Cancer. We previously reported that Trifluoperazine (TFP), an antipsychotic agent, was capable of binding to NUPR1 and inhibiting tumors growth. Unfortunately, TFP showed strong central nervous system side-effects. In this work, we undertook a multidisciplinary approach to optimize TFP, based on the synergy of computer modeling, chemical synthesis, and a variety of biophysical, biochemical and biological evaluations. A family of TFP-derived compounds was produced and the most active one, named ZZW-115, showed a dose-dependent tumor regression with no neurological effects and induced cell death mainly by Necroptosis. This study opens a new perspective for drug development against IDPs, demonstrating the possibility of successful ligand-based drug design for such challenging targets.

Keywords

Bioinformatics; Cell stress; Drug screens; Gastroenterology; Oncology.

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