Ligand-based design identifies a potent NUPR1 inhibitor exerting anticancer activity via necroptosis
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
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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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 3

ZZW-115 has strong antitumoral effect in vivo.

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ZZW-115 has strong antitumoral effect in vivo. NMRI-Foxn1nu/Foxn1nu mice...
NMRI-Foxn1nu/Foxn1nu mice (nude mice) xenografted with MiaPaCa-2 cells were separated into 5 groups of 6 mice and treated daily for 30 days with 0.5% DMSO in physiologic serum (control group) or 5, 2.5, 1.0, or 0.5 mg/kg ZZW-115 compound. Tumor volume was measured every 5 days. Mean of the volume of each treatment (A) and individual volume of each mouse (B) are shown. For each treatment, statistical significance is **P < 0.01 and ***P < 0.001 (1-way ANOVA, Tukey’s post hoc test). (C) Representative pictures of mice from control and 5 mg/kg ZZW-115 treatment groups. (D) Tumor volume of 5 mice treated with 5 mg/kg ZZW-115 measured after an additional 30 days without treatment; the arrow indicates the day the treatment was stopped. Student’s 2-tailed unpaired t test. (E) Tumor volume of nude mice xenografted with PDAC cells or C57BL/6 mice orthotopically implanted with Panc02 cells, and treated with 5 mg/kg ZZW-115 or vehicle. Tumor volume after 30 days of treatment (n = 6). (F) Representative pictures of histologic sections of the tumor xenografts or tumors from PDX1-Cre KrasG12D Ink4afl/fl, PKI mice (both from control or 5 mg/kg ZZW-115–treated mice). Scale bar: 500 μm. (G) Necrotic area in PKI mice, calculated for n = 9 mice. For each treatment, statistical significance is **P < 0.01 and ***P < 0.001 (Student’s 2-tailed unpaired t test).