{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T14:19:32Z","timestamp":1783606772445,"version":"3.55.0"},"reference-count":54,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,3]],"date-time":"2021-10-03T00:00:00Z","timestamp":1633219200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Spanish Ministry of Economy and Competitiveness and European ERDF Funds (MCIU\/AEI\/FEDER, EU)","award":["RTI2018-097991-B-I00"],"award-info":[{"award-number":["RTI2018-097991-B-I00"]}]},{"name":"Fondo de Investigaciones Sanitarias from Instituto de Salud Carlos III","award":["PI18\/00349"],"award-info":[{"award-number":["PI18\/00349"]}]},{"name":"Diputaci\u00f3n General de Arag\u00f3n","award":["E45_20R B25_20R"],"award-info":[{"award-number":["E45_20R B25_20R"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Intrinsically disordered proteins (IDPs) are emerging as attractive drug targets by virtue of their physiological ubiquity and their prevalence in various diseases, including cancer. NUPR1 is an IDP that localizes throughout the whole cell, and is involved in the development and progression of several tumors. We have previously repurposed trifluoperazine (TFP) as a drug targeting NUPR1 and, by using a ligand-based approach, designed the drug ZZW-115 starting from the TFP scaffold. Such derivative compound hinders the development of pancreatic ductal adenocarcinoma (PDAC) in mice, by hampering nuclear translocation of NUPR1. Aiming to further improve the activity of ZZW-115, here we have used an indirect drug design approach to modify its chemical features, by changing the substituent attached to the piperazine ring. As a result, we have synthesized a series of compounds based on the same chemical scaffold. Isothermal titration calorimetry (ITC) showed that, with the exception of the compound preserving the same chemical moiety at the end of the alkyl chain as ZZW-115, an increase of the length by a single methylene group (i.e., ethyl to propyl) significantly decreased the affinity towards NUPR1 measured in vitro, whereas maintaining the same length of the alkyl chain and adding heterocycles favored the binding affinity. However, small improvements of the compound affinity towards NUPR1, as measured by ITC, did not result in a corresponding improvement in their inhibitory properties and in cellulo functions, as proved by measuring three different biological effects: hindrance of the nuclear translocation of the protein, sensitization of cells against DNA damage mediated by NUPR1, and prevention of cancer cell growth. Our findings suggest that a delicate compromise between favoring ligand affinity and controlling protein function may be required to successfully design drugs against NUPR1, and likely other IDPs.<\/jats:p>","DOI":"10.3390\/biom11101453","type":"journal-article","created":{"date-parts":[[2021,10,4]],"date-time":"2021-10-04T09:24:15Z","timestamp":1633339455000},"page":"1453","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Design of Inhibitors of the Intrinsically Disordered Protein NUPR1: Balance between Drug Affinity and Target Function"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1110-764X","authenticated-orcid":false,"given":"Bruno","family":"Rizzuti","sequence":"first","affiliation":[{"name":"CNR-NANOTEC, SS Rende (CS), Department of Physics, University of Calabria, Via P. Bucci, Cubo 31 C, 87036 Rende, Cosenza, Italy"},{"name":"Instituto de Biocomputaci\u00f3n y F\u00edsica de Sistemas Complejos, Joint Units IQFR-CSIC-BIFI, and GBsC-CSIC-BIFI, Universidad de Zaragoza, 50018 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjun","family":"Lan","sequence":"additional","affiliation":[{"name":"Centre de Recherche en Canc\u00e9rologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Institut Paoli-Calmettes, Aix-Marseille Universit\u00e9, 13288 Marseille, France"},{"name":"Aix-Marseille Universit\u00e9, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille, UMR 7325, \u00abEquipe Labellis\u00e9e Ligue Contre le Cancer\u00bb, 13288 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2506-5567","authenticated-orcid":false,"given":"Patricia","family":"Santofimia-Casta\u00f1o","sequence":"additional","affiliation":[{"name":"Centre de Recherche en Canc\u00e9rologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Institut Paoli-Calmettes, Aix-Marseille Universit\u00e9, 13288 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengwei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5702-4538","authenticated-orcid":false,"given":"Adri\u00e1n","family":"Vel\u00e1zquez-Campoy","sequence":"additional","affiliation":[{"name":"Instituto de Biocomputaci\u00f3n y F\u00edsica de Sistemas Complejos, Joint Units IQFR-CSIC-BIFI, and GBsC-CSIC-BIFI, Universidad de Zaragoza, 50018 Zaragoza, Spain"},{"name":"Aragon Institute for Health Research (IIS Aragon), 50009 Zaragoza, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en el \u00c1rea Tem\u00e1tica de Enfermedades Hep\u00e1ticas y Digestivas (CIBERehd), 28029 Barcelona, Spain"},{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular y Celular, Universidad de Zaragoza, 50009 Zaragoza, Spain"},{"name":"Fundacion ARAID, Government of Aragon, 50018 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5664-1729","authenticated-orcid":false,"given":"Olga","family":"Abi\u00e1n","sequence":"additional","affiliation":[{"name":"Instituto de Biocomputaci\u00f3n y F\u00edsica de Sistemas Complejos, Joint Units IQFR-CSIC-BIFI, and GBsC-CSIC-BIFI, Universidad de Zaragoza, 50018 Zaragoza, Spain"},{"name":"Aragon Institute for Health Research (IIS Aragon), 50009 Zaragoza, Spain"},{"name":"Instituto Aragon\u00e9s de Ciencias de la Salud (IACS), 50009 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Peng","sequence":"additional","affiliation":[{"name":"Aix-Marseille Universit\u00e9, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille, UMR 7325, \u00abEquipe Labellis\u00e9e Ligue Contre le Cancer\u00bb, 13288 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4933-0428","authenticated-orcid":false,"given":"Jos\u00e9 L.","family":"Neira","sequence":"additional","affiliation":[{"name":"Instituto de Biocomputaci\u00f3n y F\u00edsica de Sistemas Complejos, Joint Units IQFR-CSIC-BIFI, and GBsC-CSIC-BIFI, Universidad de Zaragoza, 50018 Zaragoza, Spain"},{"name":"IDIBE, Universidad Miguel Hern\u00e1ndez, 03202 Elche, Alicante, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5863-7272","authenticated-orcid":false,"given":"Yi","family":"Xia","sequence":"additional","affiliation":[{"name":"Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan L.","family":"Iovanna","sequence":"additional","affiliation":[{"name":"Centre de Recherche en Canc\u00e9rologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Institut Paoli-Calmettes, Aix-Marseille Universit\u00e9, 13288 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1016\/j.sbi.2011.03.011","article-title":"Intrinsically Disordered Proteins: Regulation and Disease","volume":"21","author":"Babu","year":"2011","journal-title":"Curr. 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