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

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 2

TFP-derived compounds have antitumoral effect due to NUPR1 inhibition.

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TFP-derived compounds have antitumoral effect due to NUPR1 inhibition. (...
(A) Viability upon a 72-hour treatment with TFP-derived compounds of pancreatic cancer cells MiaPaCa-2, 02-063, LIPC, Foie8b, and HN14. (B) Viability of a panel of 11 additional pancreatic cancer cells upon a 72-hour treatment with ZZW-115. (C) NUPR1 expression values by RNA-seq are plotted against AUC. Data were statistically analyzed by simple linear regression and r2 and P values calculated. (D) Chemogram assays to test the sensitivity of the MiaPaCa-2–resistant cells to gemcitabine (Gem.) or oxaliplatin (Oxa.) after ZZW-115 treatment. (E) Viability of 2 NUPR1-WT clones and 3 NUPR1-KO clones PDAC cells upon a 24- or 72-hour treatment with 15 μM ZZW-115, or at increasing concentrations. (F) Viability of cell lines U87, A375, U2OS, SaOS-2, HT29, SK-CO-1, LS174T, H1299 and H358, HepG2, PC3, THP-1, Daudi, Jurkat and MDA-MB-231 at increasing concentrations of ZZW-115. AUC obtained from integration. Statistical significance: *P < 0.05 and **P < 0.01 compared with 0 hours of treatment; #P < 0.05, ##P < 0.01, and ###P < 0.001 compared with NUPR1-WT clones (2-way ANOVA, Bonferroni’s post hoc test). Data represent mean ± SEM, n = 3 (with technical triplicates).