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.
Highlights
Since their first description [1], 40 years of research on microtubule targeting agents (MTAs) has expanded our knowledge of biologically potent tubulin-binding compounds
Many studies led to the characterization of new microtubule targeting agent, some of which are routinely used in the clinic and a large number of which are currently under clinical development
MSAs targeting the taxane site of tubulin are, for example, able to change the conformation of the M-loop of β-tubulin. This conformational change is essential to strengthen the lateral contacts between protofilament in microtubules [4], and to revert changes induced by GTP hydrolysis at the longitudinal tubulin-tubulin interface along protofilaments [5]
Summary
Since their first description [1], 40 years of research on microtubule targeting agents (MTAs) has expanded our knowledge of biologically potent tubulin-binding compounds. One strategy commonly used to overcome non-specific side effects is to exploit antibody-drug conjugates (ADCs) to target cancer cells. This methodology can be further extended by attaching two different MTAs with different modes of action to one and the same antibody in order to decrease the chances of resistance development [10,11,12]. Quinolin-6-yloxyacetamides (QAs) were initially identified as fungicides that are highly active against several major phytopathogens [16] They constitute a chemical class of ligands that acts by inhibiting tubulin polymerization [16].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
