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Int. J. Mol. Sci. 2017, 18(7), 1336;

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

Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, CH-5232 Villigen, Switzerland
Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain
Chemical Research, Syngenta Crop Protection AG, Schaffhauserstrasse 101, CH-4332 Stein, Switzerland
Authors to whom correspondence should be addressed.
Received: 26 April 2017 / Revised: 9 June 2017 / Accepted: 18 June 2017 / Published: 22 June 2017
(This article belongs to the Special Issue Microtubule-Targeting Agents)
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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. View Full-Text
Keywords: microtubules; microtubule targeting agents; quinolin-6-yloxyacetamides; multidrug resistance microtubules; microtubule targeting agents; quinolin-6-yloxyacetamides; multidrug resistance

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Sharma, A.; Sáez-Calvo, G.; Olieric, N.; de Asís Balaguer, F.; Barasoain, I.; Lamberth, C.; Díaz, J.F.; Steinmetz, M.O. Quinolin-6-Yloxyacetamides Are Microtubule Destabilizing Agents That Bind to the Colchicine Site of Tubulin. Int. J. Mol. Sci. 2017, 18, 1336.

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