Quinolin-6-yloxyacetamides are microtubule destabilizing agents that bind to the colchicine site of tubulin

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.This work was supported by grants from Spanish Ministerio de Economía y Competitividad (BFU2016-75319-R (AEI/FEDER, UE) to J. Fernando Díaz) and from the Swiss National Science Foundation (31003A_166608 to Michel O. Steinmetz). The authors acknowledge networking contribution by the COST (European Cooperation in Science and Technology) Action CM1407 “Challenging organic syntheses inspired by nature—from natural products chemistry to drug discovery”. X-ray data were collected at beamline X06DA of the Swiss Light Source (Paul Scherrer Institut, Villigen, Switzerland). Ashwani Sharma was supported by an EMBO (European Molecular Biology Organization) Long Term Fellowship, J. Fernando Díaz is member of the CIB Intramural Program “Molecular Machines for Better Life” (MACBET)