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Ligand-based design identifies a potent NUPR1 inhibitor exerting anticancer activity via necroptosis
Patricia Santofimia-Castaño, … , José L. Neira, Juan Iovanna
Patricia Santofimia-Castaño, … , José L. Neira, Juan Iovanna
Published March 28, 2019
Citation Information: J Clin Invest. 2019;129(6):2500-2513. https://doi.org/10.1172/JCI127223.
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Research Article Gastroenterology Oncology

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

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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 IDPs have dynamic structure features and conventional drug design is not applicable. NUPR1 is an IDP that plays an important role in pancreatic cancer. We previously reported that trifluoperazine (TFP), an antipsychotic agent, was capable of binding to NUPR1 and inhibiting tumor growth. Unfortunately, TFP showed strong central nervous system side effects. In the present 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, ZZW-115, showed a dose-dependent tumor regression with no neurological effects and an ability to induce 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.

Authors

Patricia Santofimia-Castaño, Yi Xia, Wenjun Lan, Zhengwei Zhou, Can Huang, Ling Peng, Philippe Soubeyran, Adrián Velázquez-Campoy, Olga Abián, Bruno Rizzuti, José L. Neira, Juan Iovanna

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Figure 1

Synthesis of the compounds, and docking and biophysical characterization of NUPR1 to the TFP-derived compounds.

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Synthesis of the compounds, and docking and biophysical characterization...
(A) Docking of TFP to short fragments of NUPR1 sequence (in different colors), mimicking potential binding locations. The phenothiazine and trifluoromethyl groups of TFP are critical for anchoring, whereas the rest of the structure contributes less. (B) Example of simulation of ZZW-115 (a single representative structure is shown in gray) in complex with sequence segments of NUPR1 (ensembles are in gradients of color, from red to blue); the labels indicate the central protein residue for each of the two 7-residue fragments. (C) Structure of the synthesized TFP-derived compounds. (D) Fluorescence ANS spectra in the presence or absence of ZZW-115 (left) and ZZW-119 (right) for the complex between both molecules (black) and for that obtained from the addition of the spectra of both isolated molecules: NUPR1 and the TFP-derived compound (blue). Experiments were performed in 20 mM sodium phosphate pH 7.0 at 25°C. (E) Calorimetric titrations corresponding to the interaction of ZZW-115 (left) and ZZW-119 (right) with NUPR1. Thermograms (thermal power as a function of time) are shown on the top, and binding isotherms (ligand-normalized heat effects as a function of molar ratio) are shown on the bottom. Experiments were performed at 25°C in sodium phosphate 20 mM, pH 7, 2% DMSO, with 20 μM NUPR1 in the calorimetric cell and 200 μM compound in the titrating syringe, using an Auto-iTC200 instrument (MicroCal-Malvern Panalytical).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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