A fluorescence anisotropy assay to discover and characterize ligands targeting the maytansine site of tubulin.
Prota, Andrea E
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Menchon, G., Prota, A. E., Lucena-Agell, D., Bucher, P., Jansen, R., Irschik, H., Müller, R., et al. (2018). A fluorescence anisotropy assay to discover and characterize ligands targeting the maytansine site of tubulin.. Nature communications, 9 (1), 2106. https://doi.org/10.1038/s41467-018-04535-8
Microtubule-targeting agents (MTAs) like taxol and vinblastine are amongst the most successful chemotherapeutic drugs against cancer. Here, we describe a fluorescence anisotropy-based assay that specifically probes for ligands targeting the recently discovered maytansine-site of tubulin. Using this assay, we have determined the dissociation constants of known maytansine-site ligands, including the pharmacologically active degradation product of the clinical antibody-drug conjugate trastuzumab emtansine. In addition, we discovered that the two natural products spongistatin-1 and disorazole Z with established cellular potency bind to the maytansine-site on -tubulin. The high resolution crystal structures of spongistatin-1 and disorazole Z in complex with tubulin allowed the definition of a novel sub-site adjacent to the pocket shared by all maytansine-site ligands, which could be exploitable as a distinct, separate target site for small molecules. Our study provides a basis for the discovery and development of next generation MTAs for the treatment of cancer.
Microtubules, Animals, Humans, Macrolides, Maytansine, Oxazoles, Tubulin, Antineoplastic Agents, Ligands, Fluorescence Polarization, Binding Sites, Trastuzumab
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External DOI: https://doi.org/10.1038/s41467-018-04535-8
This record's URL: https://www.repository.cam.ac.uk/handle/1810/278957
Attribution 4.0 International
Licence URL: http://creativecommons.org/licenses/by/4.0/
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