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

15 pags, 5 figs, 2 pagsIntrinsically 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.This work was supported by La Ligue Contre le Cancer, INCa, Canceropole PACA and INSERM (to JI); Miguel Servet Program from Instituto de Salud Carlos III (CPII13/00017 to OA); Fondo de Investigaciones Sanitarias (PI15/00663 and PI18/00343 to OA); Spanish Ministry of Economy and Competitiveness (BFU201678232-P to AVC, CTQ2015-64445-R to JLN); Diputacion General de Aragon (Protein Targets Group B89 to AVC, and Digestive Pathology Group B01 to OA); Generalitat Valenciana (Prometeo 018/2013 to JLN); Centro de Investigacion Biomedica en Red en Enfermedades Hepaticas y Digestivas (CIBERehd); Fundacion Alfonso Martin-Escudero and Fondation de France (to PSC); China Scholarship Council (to WL and CH); Programme XU GUANGQI (to YX and JI); National Natural Science Foundation of China (81502920) and the Fundamental Research Funds for the Central Universities (106112017CDJQJ468823) (both to YX). BR acknowledges hospitality from the European Magnetic Resonance Center (CERM), Sesto Fiorentino, Florence, Italy.Peer reviewe