Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 18, Issue 7, Pages -Publisher
MDPI
DOI: 10.3390/ijms18071336
Keywords
microtubules; microtubule targeting agents; quinolin-6-yloxyacetamides; multidrug resistance
Funding
- Spanish Ministerio de Economia y Competitividad (AEI/FEDER, UE) [BFU2016-75319-R]
- Swiss National Science Foundation [31003A_166608]
- EMBO (European Molecular Biology Organization)
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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.
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