Design of inhibitors of the intrinsically disordered protein NUPR1: balance between drug affinity and target function

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 sever...

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Autores: Rizzuti, Bruno, Lan, Wenjun, Santofimia-Castaño, Patricia, Zhou, Zhengwei, Velázquez-Campoy, Adrián, Abian, Olga, Peng, Ling, Neira, José L., Xia, Yi, Iovanna, Juan Lucio
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/259158
Acceso en línea:http://hdl.handle.net/10261/259158
https://api.elsevier.com/content/abstract/scopus_id/85116157221
Access Level:acceso abierto
Palabra clave:Biological assays
Drug discovery
Intrinsically disordered proteins
Ligand-based design
Nuclear protein 1
Isothermal titration calorimetry
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oai_identifier_str oai:digital.csic.es:10261/259158
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Design of inhibitors of the intrinsically disordered protein NUPR1: balance between drug affinity and target function
title Design of inhibitors of the intrinsically disordered protein NUPR1: balance between drug affinity and target function
spellingShingle Design of inhibitors of the intrinsically disordered protein NUPR1: balance between drug affinity and target function
Rizzuti, Bruno
Biological assays
Drug discovery
Intrinsically disordered proteins
Ligand-based design
Nuclear protein 1
Isothermal titration calorimetry
title_short Design of inhibitors of the intrinsically disordered protein NUPR1: balance between drug affinity and target function
title_full Design of inhibitors of the intrinsically disordered protein NUPR1: balance between drug affinity and target function
title_fullStr Design of inhibitors of the intrinsically disordered protein NUPR1: balance between drug affinity and target function
title_full_unstemmed Design of inhibitors of the intrinsically disordered protein NUPR1: balance between drug affinity and target function
title_sort Design of inhibitors of the intrinsically disordered protein NUPR1: balance between drug affinity and target function
dc.creator.none.fl_str_mv Rizzuti, Bruno
Lan, Wenjun
Santofimia-Castaño, Patricia
Zhou, Zhengwei
Velázquez-Campoy, Adrián
Abian, Olga
Peng, Ling
Neira, José L.
Xia, Yi
Iovanna, Juan Lucio
author Rizzuti, Bruno
author_facet Rizzuti, Bruno
Lan, Wenjun
Santofimia-Castaño, Patricia
Zhou, Zhengwei
Velázquez-Campoy, Adrián
Abian, Olga
Peng, Ling
Neira, José L.
Xia, Yi
Iovanna, Juan Lucio
author_role author
author2 Lan, Wenjun
Santofimia-Castaño, Patricia
Zhou, Zhengwei
Velázquez-Campoy, Adrián
Abian, Olga
Peng, Ling
Neira, José L.
Xia, Yi
Iovanna, Juan Lucio
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
Ligue Nationale contre le Cancer (France)
Canceropole PACA
Ministerio de Ciencia, Innovación y Universidades (España)
European Commission
Instituto de Salud Carlos III
Diputación General de Aragón
Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España)
Fondation de France
China Scholarship Council
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Biological assays
Drug discovery
Intrinsically disordered proteins
Ligand-based design
Nuclear protein 1
Isothermal titration calorimetry
topic Biological assays
Drug discovery
Intrinsically disordered proteins
Ligand-based design
Nuclear protein 1
Isothermal titration calorimetry
description 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.
publishDate 2021
dc.date.none.fl_str_mv 2021
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/259158
https://api.elsevier.com/content/abstract/scopus_id/85116157221
url http://hdl.handle.net/10261/259158
https://api.elsevier.com/content/abstract/scopus_id/85116157221
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-097991-B-I00
Biomolecules
https://doi.org/10.3390/biom11101453
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling Design of inhibitors of the intrinsically disordered protein NUPR1: balance between drug affinity and target functionRizzuti, BrunoLan, WenjunSantofimia-Castaño, PatriciaZhou, ZhengweiVelázquez-Campoy, AdriánAbian, OlgaPeng, LingNeira, José L.Xia, YiIovanna, Juan LucioBiological assaysDrug discoveryIntrinsically disordered proteinsLigand-based designNuclear protein 1Isothermal titration calorimetryIntrinsically 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.This work was supported by Spanish Ministry of Economy and Competitiveness and European ERDF Funds (MCIU/AEI/FEDER, EU) [RTI2018-097991-B-I00 to J.L.N.]; La Ligue Contre le Cancer, INCa, Canceropole PACA and INSERM to JLI; Fondo de Investigaciones Sanitarias from Instituto de Salud Carlos III, and European Union (ERDF/ESF, 'Investing in your future') (PI18/00349 to O.A.); Diputacion General de Aragon ('Protein Targets and Bioactive Compounds Group' E45_20R to A.V.-C., 'Digestive Pathology Group' B25_20R to O.A.); Centro de Investigacion Biomedica en Red en Enfermedades Hepaticas y Digestivas (CIBERehd) (O.A. and A.V.-C.); CAI YUANPEI Scholarship (201906050187) to Y.X.; and Jeunes Talents France-Chine Program (JTFC) to Y.X. P.S.-C. was supported by Fondation de France; and W.L. by China Scholarship Council.Peer reviewedMultidisciplinary Digital Publishing InstituteMinisterio de Economía y Competitividad (España)Ligue Nationale contre le Cancer (France)Canceropole PACAMinisterio de Ciencia, Innovación y Universidades (España)European CommissionInstituto de Salud Carlos IIIDiputación General de AragónCentro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España)Fondation de FranceChina Scholarship CouncilConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202220222021info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/259158https://api.elsevier.com/content/abstract/scopus_id/85116157221reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-097991-B-I00Biomoleculeshttps://doi.org/10.3390/biom11101453Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2591582026-05-22T06:33:51Z
score 15.81155

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