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Nature communications v.9 no.1, 2018년, pp.2106 - 2106   SCI SCIE
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A fluorescence anisotropy assay to discover and characterize ligands targeting the maytansine site of tubulin

Menchon, Grégory (Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, Villigen PSI, 5232, Switzerland ) ; Prota, Andrea E. (Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, Villigen PSI, 5232, Switzerland ) ; Lucena-Agell, Daniel (Chemical and Physical Biology, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas CIB–CSIC, Madrid, 28040, Spain ) ; Bucher, Pascal (Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zürich, Zürich, 8093, Switzerland ) ; Jansen, Rolf (Abteilung Mikrobielle Wirkstoffe, Helmholtz Zentrum für Infektionsforschung, Braunschweig, 38124, Germany ) ; Irschik, Herbert (Abteilung Mikrobielle Wirkstoffe, Helmholtz Zentrum für Infektionsforschung, Braunschweig, 38124, Germany ) ; Müller, Rolf (Department Microbial Natural Products and Department of Pharmacy at Saarland University, Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research, Saarbrücken, 66123, ) ; Paterson, Ian ; Díaz, J. Fernando ; Altmann, Karl-Heinz ; Steinmetz, Michel O. ;
  • 초록  

    Microtubule-targeting agents (MTAs) like taxol and vinblastine are among 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 β-tubulin. The high-resolution crystal structures of spongistatin-1 and disorazole Z in complex with tubulin allowed the definition of an additional 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.


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