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

• DOI: 10.1073/pnas.1408124111
• Publication Date: 2014-08-12T06:59:19Z
• Authors: Andrea E. Prota; Katja Bargsten; J. Fernando Diaz; May Marsh; Carmen Cuevas; Marc Liniger; Christian Neuhaus; Jose M. Andreu; Karl-Heinz Altmann; Michel O. Steinmetz
• Keywords: Mechanism of Action; Vinca

Significance 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 proliferation. Here we have analyzed three structurally unrelated destabilize microtubules, using X-ray crystallography. The data reveal new tubulin-binding site these drugs, renders mechanism action distinct other types microtubule assembly inhibitors. Similar interactions with observed all ligands, thus defining common pharmacophore. Our results offer an opportunity rational design potent modulators development more efficient therapies.