Triazolopyrimidines Are Microtubule-Stabilizing Agents that Bind the Vinca Inhibitor Site of Tubulin

53 p.-7 fig.+ 7 p.-1 tab.supl.-6 fig.supl. Saez Calvo, Gonzalo et al.

Bibliographic Details
Authors: Sáez-Calvo, Gonzalo, Balaguer, Francisco de Asís, Barasoain, Isabel, Rodríguez-Salarichs, Javier, Muñoz-Hernández, Hugo, Berbís, Manuel Álvaro, Peñalva, Miguel Ángel, Matesanz, Ruth, Canales, Ángeles, Jiménez-Barbero, Jesús, Andreu, José Manuel, Díaz, José Fernando
Format: article
Status:Versión aceptada para publicación
Publication Date:2017
Country:España
Institution:Consejo Superior de Investigaciones Científicas (CSIC)
Repository:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/152590
Online Access:http://hdl.handle.net/10261/152590
Access Level:Open access
Keyword:Tubulin
Microtubules
Microtubule‐targeting agents
Antitumourals
Resistance to chemotherapy
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spelling Triazolopyrimidines Are Microtubule-Stabilizing Agents that Bind the Vinca Inhibitor Site of TubulinTriazolopyrimidines stabilize microtubules by binding to the vinca inhibitor site of tubulinSáez-Calvo, GonzaloBalaguer, Francisco de AsísBarasoain, IsabelRodríguez-Salarichs, JavierMuñoz-Hernández, HugoBerbís, Manuel ÁlvaroPeñalva, Miguel ÁngelMatesanz, RuthCanales, ÁngelesJiménez-Barbero, JesúsAndreu, José ManuelDíaz, José FernandoTubulinMicrotubulesMicrotubule‐targeting agentsAntitumouralsResistance to chemotherapy53 p.-7 fig.+ 7 p.-1 tab.supl.-6 fig.supl. Saez Calvo, Gonzalo et al.Microtubule-targeting agents (MTAs) are some of the clinically most successful anti-cancer drugs. Unfortunately, instances of multidrug resistances to MTA have been reported, which highlights the need for developing MTAs with different mechanistic properties. One less explored class of MTAs are [1,2,4]triazolo[1,5-a]pyrimidines (TPs). These cytotoxic compounds are microtubule-stabilizing agents that inexplicably bind to vinblastine binding site on tubulin, which is typically targeted by microtubule-destabilizing agents. Here we used cellular, biochemical, and structural biology approaches to address this apparent discrepancy. Our results establish TPs as vinca-site microtubule-stabilizing agents that promote longitudinal tubulin contacts in microtubules, in contrast to classical microtubule-stabilizing agents that primarily promote lateral contacts. Additionally we observe that TPs studied here are not affected by p-glycoprotein overexpression, and suggest that TPs are promising ligands against multidrug-resistant cancer cells.This work was supported in part by grants BFU2016‐75319‐R (AEI/FEDER, UE) (JFD), BFU2014‐51823‐R (to JMA) from Ministerio de Economia y Competitividad and 31003A_166608 from the Swiss National Science Foundation (M.O.S.). The authors acknowledge networking contribution by the COST Action CM1407 “Challenging organic syntheses inspired by nature ‐ from natural products chemistry to drug discovery”. The SAXS experiments were performed at BL11‐NCD beamline at ALBA Synchrotron with the collaboration of ALBA staff. X‐ray data were collected at beamline X06DA of the Swiss Light Source (Paul Scherrer Institut, Villigen, Switzerland).Peer reviewedElsevierMinisterio de Economía y Competitividad (España)Swiss National Science FoundationConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]201720172017info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Postprintinfo:eu-repo/semantics/acceptedVersionhttp://hdl.handle.net/10261/152590reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2016‐75319‐Rinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2014‐51823‐Rhttps://doi.org/10.1016/j.chembiol.2017.05.016Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1525902026-05-22T06:33:51Z
dc.title.none.fl_str_mv Triazolopyrimidines Are Microtubule-Stabilizing Agents that Bind the Vinca Inhibitor Site of Tubulin
Triazolopyrimidines stabilize microtubules by binding to the vinca inhibitor site of tubulin
title Triazolopyrimidines Are Microtubule-Stabilizing Agents that Bind the Vinca Inhibitor Site of Tubulin
spellingShingle Triazolopyrimidines Are Microtubule-Stabilizing Agents that Bind the Vinca Inhibitor Site of Tubulin
Sáez-Calvo, Gonzalo
Tubulin
Microtubules
Microtubule‐targeting agents
Antitumourals
Resistance to chemotherapy
title_short Triazolopyrimidines Are Microtubule-Stabilizing Agents that Bind the Vinca Inhibitor Site of Tubulin
title_full Triazolopyrimidines Are Microtubule-Stabilizing Agents that Bind the Vinca Inhibitor Site of Tubulin
title_fullStr Triazolopyrimidines Are Microtubule-Stabilizing Agents that Bind the Vinca Inhibitor Site of Tubulin
title_full_unstemmed Triazolopyrimidines Are Microtubule-Stabilizing Agents that Bind the Vinca Inhibitor Site of Tubulin
title_sort Triazolopyrimidines Are Microtubule-Stabilizing Agents that Bind the Vinca Inhibitor Site of Tubulin
dc.creator.none.fl_str_mv Sáez-Calvo, Gonzalo
Balaguer, Francisco de Asís
Barasoain, Isabel
Rodríguez-Salarichs, Javier
Muñoz-Hernández, Hugo
Berbís, Manuel Álvaro
Peñalva, Miguel Ángel
Matesanz, Ruth
Canales, Ángeles
Jiménez-Barbero, Jesús
Andreu, José Manuel
Díaz, José Fernando
author Sáez-Calvo, Gonzalo
author_facet Sáez-Calvo, Gonzalo
Balaguer, Francisco de Asís
Barasoain, Isabel
Rodríguez-Salarichs, Javier
Muñoz-Hernández, Hugo
Berbís, Manuel Álvaro
Peñalva, Miguel Ángel
Matesanz, Ruth
Canales, Ángeles
Jiménez-Barbero, Jesús
Andreu, José Manuel
Díaz, José Fernando
author_role author
author2 Balaguer, Francisco de Asís
Barasoain, Isabel
Rodríguez-Salarichs, Javier
Muñoz-Hernández, Hugo
Berbís, Manuel Álvaro
Peñalva, Miguel Ángel
Matesanz, Ruth
Canales, Ángeles
Jiménez-Barbero, Jesús
Andreu, José Manuel
Díaz, José Fernando
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
Swiss National Science Foundation
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Tubulin
Microtubules
Microtubule‐targeting agents
Antitumourals
Resistance to chemotherapy
topic Tubulin
Microtubules
Microtubule‐targeting agents
Antitumourals
Resistance to chemotherapy
description 53 p.-7 fig.+ 7 p.-1 tab.supl.-6 fig.supl. Saez Calvo, Gonzalo et al.
publishDate 2017
dc.date.none.fl_str_mv 2017
2017
2017
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Postprint
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/152590
url http://hdl.handle.net/10261/152590
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2016‐75319‐R
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2014‐51823‐R
https://doi.org/10.1016/j.chembiol.2017.05.016
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
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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score 15,812455

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