A new tubulin binding site for microtubule-destabilizing antitumor drugs

A new tubulin binding site for microtubule-destabilizing antitumor drugs


CIB researchers have taken part in the discovery a new anticancer target in tubulin. Microtubules are dynamic protein filaments assembled from tubulin subunits, which play a key role for cell division. Ligands that target microtubules and affect their dynamics belong to the most successful classes of chemotherapeutic drugs against cancer by inhibiting cell proliferation.

Three structurally unrelated drugs that destabilize microtubules have been analyzed using X-ray crystallography in this study published by PNAS (Prota et al., 2014). The high-resolution crystal structure of the complex between tubulin and maytansine, which is part of an antibody conjugate that is approved by the US Food and Drug Administration for the treatment of advanced breast cancer, has been determined. 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. The crystal structures of tubulin in complex with both a variant of rhizoxin and the phase 1 drug PM060184 have also been solved. Consistent with biochemical and mutagenesis data, the two compounds bound to the same site as maytansine and the structures revealed a common pharmacophore for the three ligands. These 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 drugs for the treatmentof cancer.

This work is continuation of a study in which CIB researchers from the groups of Fernando Diaz, Miguel Angel Peñalva, Jesus Jimenez-Barbero and Jose Manuel Andreu in collaboration with PharmaMar, determined the target and distinct mechanism of action of the new antitumor compound of marine origin PM060184 (Pera et al., 2013)