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

Overview of attention for article published in Cell Chemical Biology, June 2017
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Title
Triazolopyrimidines Are Microtubule-Stabilizing Agents that Bind the Vinca Inhibitor Site of Tubulin
Published in
Cell Chemical Biology, June 2017
DOI 10.1016/j.chembiol.2017.05.016
Pubmed ID
Authors

Sáez-Calvo, Gonzalo, Sharma, Ashwani, Balaguer, Francisco de Asís, Barasoain, Isabel, Rodríguez-Salarichs, Javier, Olieric, Natacha, Muñoz-Hernández, Hugo, Berbís, Manuel Álvaro, Wendeborn, Sebastian, Peñalva, Miguel Angel, Matesanz, Ruth, Canales, Ángeles, Prota, Andrea Enrico, Jímenez-Barbero, Jesús, Andreu, José Manuel, Lamberth, Clemens, Steinmetz, Michel Olivier, Díaz, José Fernando, Gonzalo Sáez-Calvo, Ashwani Sharma, Francisco de Asís Balaguer, Isabel Barasoain, Javier Rodríguez-Salarichs, Natacha Olieric, Hugo Muñoz-Hernández, Manuel Álvaro Berbís, Sebastian Wendeborn, Miguel Angel Peñalva, Ruth Matesanz, Ángeles Canales, Andrea Enrico Prota, Jesús Jímenez-Barbero, José Manuel Andreu, Clemens Lamberth, Michel Olivier Steinmetz, José Fernando Díaz

Abstract

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.

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Mendeley readers

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Geographical breakdown

Country Count As %
Unknown 6 100%

Demographic breakdown

Readers by professional status Count As %
Other 3 50%
Student > Ph. D. Student 2 33%
Researcher 1 17%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 2 33%
Agricultural and Biological Sciences 2 33%
Design 2 33%