A fluorescence anisotropy assay to discover and characterize ligands targeting the maytansine site of tubulin

Grégory Menchon, Andrea E. Prota, Daniel Lucena-Agell, Pascal Bucher, Rolf Jansen, Herbert Irschik, Rolf Müller, Ian Paterson, J. Fernando Díaz, Karl-Heinz Altmann and Michel O. Steinmetz ()
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Grégory Menchon: Paul Scherrer Institut
Andrea E. Prota: Paul Scherrer Institut
Daniel Lucena-Agell: Consejo Superior de Investigaciones Cientificas CIB–CSIC
Pascal Bucher: ETH Zürich
Rolf Jansen: Helmholtz Zentrum für Infektionsforschung
Herbert Irschik: Helmholtz Zentrum für Infektionsforschung
Rolf Müller: Helmholtz Centre for Infection Research
Ian Paterson: Cambridge University
J. Fernando Díaz: Consejo Superior de Investigaciones Cientificas CIB–CSIC
Karl-Heinz Altmann: ETH Zürich
Michel O. Steinmetz: Paul Scherrer Institut

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-04535-8

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