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

doi:10.3390/ijms18071336

Paper

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

Published Jun 22, 2017 · Ashwani Sharma, Gonzalo Sáez-Calvo, N. Olieric

International Journal of Molecular Sciences

Q1 SJR score

10

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0

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Abstract

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.

Study Snapshot

Quinolin-6-yloxyacetamides (QAs) are potent anti-proliferative agents against human cancer cells, disrupting the microtubule cytoskeleton and causing severe mitotic defects, binding to the colchicine site on tubulin.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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

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