title: A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs.
abstract: 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.
authors.affiliation: Department of Biology and Chemistry, Laboratory of Biomolecular Research, Paul Scherrer Institut, 5232 Villigen PSI, Switzerland;
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Prota
authors.affiliation: Department of Biology and Chemistry, Laboratory of Biomolecular Research, Paul Scherrer Institut, 5232 Villigen PSI, Switzerland;
authors.forename: Katja
authors.initials: K
authors.lastname: Bargsten
authors.affiliation: Chemical and Physical Biology, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas CIB-CSIC, 28040 Madrid, Spain;
authors.forename: J Fernando
authors.initials: JF
authors.lastname: Diaz
authors.affiliation: Swiss Light Source, Paul Scherrer Institut, 5232 Villigen PSI, Switzerland;
authors.forename: May
authors.initials: M
authors.lastname: Marsh
authors.affiliation: PharmaMar S.A., 28770 Madrid, Spain; and.
authors.forename: Carmen
authors.initials: C
authors.lastname: Cuevas
authors.affiliation: Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zürich, 8093 Zürich, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Liniger
authors.affiliation: Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zürich, 8093 Zürich, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Neuhaus
authors.affiliation: Chemical and Physical Biology, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas CIB-CSIC, 28040 Madrid, Spain;
authors.forename: Jose M
authors.initials: JM
authors.lastname: Andreu
authors.affiliation: Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zürich, 8093 Zürich, Switzerland.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Altmann
authors.affiliation: Department of Biology and Chemistry, Laboratory of Biomolecular Research, Paul Scherrer Institut, 5232 Villigen PSI, Switzerland; michel.steinmetz@psi.ch.
authors.forename: Michel O
authors.initials: MO
authors.lastname: Steinmetz
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000627:therapeutic use; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy; D002417:Cattle; D017321:Clinical Trials, Phase I as Topic; D018360:Crystallography, X-Ray; D005260:Female; D006801:Humans; D018942:Macrolides / Q000737:chemistry* / Q000627:therapeutic use; D008453:Maytansine / Q000737:chemistry* / Q000627:therapeutic use; D008870:Microtubules / Q000737:chemistry*; D061065:Polyketides / Q000737:chemistry* / Q000627:therapeutic use; D011753:Pyrones / Q000737:chemistry* / Q000627:therapeutic use; D014404:Tubulin / Q000737:chemistry*; D050257:Tubulin Modulators / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D018942:Macrolides; D061065:Polyketides; D011753:Pyrones; D014404:Tubulin; D050257:Tubulin Modulators; D008453:Maytansine; C586200:plocabulin; C041443:rhizoxin
keywords: X-ray crystallography; drug mechanism; microtubule-targeting agents
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