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Quinolin-6-Yloxyacetamides Are Microtubule Destabilizing Agents That Bind to the Colchicine Site of Tubulin.

  • Sharma A Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, CH-5232 Villigen, Switzerland. ashwani.sharma@psi.ch.
  • Sáez-Calvo G Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain. g.saez.calvo@gmail.com.
  • Olieric N Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, CH-5232 Villigen, Switzerland. natacha.olieric@psi.ch.
  • de Asís Balaguer F Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain. pacobal@cib.csic.es.
  • Barasoain I Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain. i.barasoain@cib.csic.es.
  • Lamberth C Chemical Research, Syngenta Crop Protection AG, Schaffhauserstrasse 101, CH-4332 Stein, Switzerland. clemens.lamberth@syngenta.com.
  • Díaz JF Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain. fer@cib.csic.es.
  • Steinmetz MO Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, CH-5232 Villigen, Switzerland. michel.steinmetz@psi.ch.
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  • 2017-06-23
Published in:
  • International journal of molecular sciences. - 2017
microtubule targeting agents
microtubules
multidrug resistance
quinolin-6-yloxyacetamides
Animals
Antineoplastic Agents
Cattle
Cell Line, Tumor
Cell Proliferation
Colchicine
Humans
Molecular Docking Simulation
Neoplasms
Quinolines
Tubulin
Tubulin Modulators
English Quinolin-6-yloxyacetamides (QAs) are a chemical class of tubulin polymerization inhibitors that were initially identified as fungicides. Here, we report that QAs are potent anti-proliferative agents against human cancer cells including ones that are drug-resistant. QAs act by disrupting the microtubule cytoskeleton and by causing severe mitotic defects. We further demonstrate that QAs inhibit tubulin polymerization in vitro. The high resolution crystal structure of the tubulin-QA complex revealed that QAs bind to the colchicine site on tubulin, which is targeted by microtubule-destabilizing agents such as colchicine and nocodazole. Together, our data establish QAs as colchicine-site ligands and explain the molecular mechanism of microtubule destabilization by this class of compounds. They further extend our structural knowledge on antitubulin agents and thus should aid in the development of new strategies for the rational design of ligands against multidrug-resistant cancer cells.
Language
  • English
Open access status
gold
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Persistent URL
https://sonar.ch/global/documents/278426
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