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High-affinity ligands of the colchicine domain in tubulin based on a structure-guided design

AuthorsBueno, Oskía; Estévez Gallego, J.; Martins, S.; Prota, Andrea E.; Gago, Federico ; Gómez-SanJuan, Asier; Camarasa Rius, María José ; Barasoain, Isabel ; Steinmetz, Michel O.; Díaz, Fernando J.; Peréz-Pérez, María-Jesús ; Liekens, Sandra; Priego, Eva María
Issue Date2018
PublisherNature Publishing Group
CitationScientific Reports 8: 4242 (2018)
AbstractMicrotubule-targeting agents that bind at the colchicine-site of tubulin are of particular interest in antitumoral therapy due to their dual mechanism of action as antimitotics and vascular disrupting agents. Cyclohexanediones derivatives have been described as a new family of colchicine-domain binders with an association constant to tubulin similar to that of colchicine. Here, the highresolution structures of tubulin in complex with cyclohexanediones TUB015 and TUB075 were solved by X-ray crystallography. A detailed analysis of the tubulin-TUB075 interaction by means of computational affinity maps allowed the identification of two additional regions at the binding site that were addressed with the design and synthesis of a new series of cyclohexanediones with a distal 2-substituted benzofurane. These new compounds showed potent antiproliferative activity with IC50 values in the nM range, arrested cell cycle progression at the G2/M phase and induced apoptosis at sub μM concentrations. Moreover, they caused the destruction of a preformed vascular network in vitro and inhibited the migration of endothelial cells at non-toxic concentrations. Finally, these compounds displayed high affinity for tubulin as substantiated by a Kb value of 2.87 × 108 M−1 which, to the best of our knowledge, represents the highest binding constant measured to date for a colchicine-domain ligand.
Publisher version (URL)http://dx.doi.org/10.1038/s41598-018-22382-x
Identifiersdoi: 10.1038/s41598-018-22382-x
issn: 2045-2322
e-issn: 2045-2322
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