Sharma Ashwani, Sáez-Calvo Gonzalo, Olieric Natacha, de Asís Balaguer Francisco, Barasoain Isabel, Lamberth Clemens, Díaz J Fernando, Steinmetz Michel O
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.
Int J Mol Sci. 2017 Jun 22;18(7):1336. doi: 10.3390/ijms18071336.
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.
喹啉-6-基氧基乙酰胺（QAs）是一类最初被鉴定为杀菌剂的微管蛋白聚合抑制剂。在此，我们报告QAs是针对包括耐药癌细胞在内的人类癌细胞的强效抗增殖剂。QAs通过破坏微管细胞骨架并导致严重的有丝分裂缺陷来发挥作用。我们进一步证明QAs在体外抑制微管蛋白聚合。微管蛋白-QA复合物的高分辨率晶体结构表明，QAs与微管蛋白上的秋水仙碱位点结合，该位点是秋水仙碱和诺考达唑等微管破坏剂的作用靶点。总之，我们的数据将QAs确立为秋水仙碱位点配体，并解释了这类化合物使微管不稳定的分子机制。它们进一步扩展了我们对抗微管蛋白剂的结构认识，因此应有助于开发针对多药耐药癌细胞的配体合理设计新策略。
