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A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs.

  • Prota AE Department of Biology and Chemistry, Laboratory of Biomolecular Research, Paul Scherrer Institut, 5232 Villigen PSI, Switzerland;
  • Bargsten K Department of Biology and Chemistry, Laboratory of Biomolecular Research, Paul Scherrer Institut, 5232 Villigen PSI, Switzerland;
  • Diaz JF Chemical and Physical Biology, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas CIB-CSIC, 28040 Madrid, Spain;
  • Marsh M Swiss Light Source, Paul Scherrer Institut, 5232 Villigen PSI, Switzerland;
  • Cuevas C PharmaMar S.A., 28770 Madrid, Spain; and.
  • Liniger M Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zürich, 8093 Zürich, Switzerland.
  • Neuhaus C Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zürich, 8093 Zürich, Switzerland.
  • Andreu JM Chemical and Physical Biology, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas CIB-CSIC, 28040 Madrid, Spain;
  • Altmann KH Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zürich, 8093 Zürich, Switzerland.
  • Steinmetz MO Department of Biology and Chemistry, Laboratory of Biomolecular Research, Paul Scherrer Institut, 5232 Villigen PSI, Switzerland; michel.steinmetz@psi.ch.
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  • 2014-08-13
Published in:
  • Proceedings of the National Academy of Sciences of the United States of America. - 2014
X-ray crystallography
drug mechanism
microtubule-targeting agents
Animals
Antibiotics, Antineoplastic
Antineoplastic Agents, Phytogenic
Binding Sites
Breast Neoplasms
Cattle
Clinical Trials, Phase I as Topic
Crystallography, X-Ray
Female
Humans
Macrolides
Maytansine
Microtubules
Polyketides
Pyrones
Tubulin
Tubulin Modulators
English The recent success of antibody-drug conjugates (ADCs) in the treatment of cancer has led to a revived interest in microtubule-destabilizing agents. Here, we determined the high-resolution crystal structure of the complex between tubulin and maytansine, which is part of an ADC that is approved by the US Food and Drug Administration (FDA) for the treatment of advanced breast cancer. We found that the drug binds to a site on β-tubulin that is distinct from the vinca domain and that blocks the formation of longitudinal tubulin interactions in microtubules. We also solved crystal structures of tubulin in complex with both a variant of rhizoxin and the phase 1 drug PM060184. Consistent with biochemical and mutagenesis data, we found that the two compounds bound to the same site as maytansine and that the structures revealed a common pharmacophore for the three ligands. Our results delineate a distinct molecular mechanism of action for the inhibition of microtubule assembly by clinically relevant agents. They further provide a structural basis for the rational design of potent microtubule-destabilizing agents, thus opening opportunities for the development of next-generation ADCs for the treatment of cancer.
Language
  • English
Open access status
bronze
Identifiers
Persistent URL
https://sonar.ch/global/documents/167988
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