High-affinity ligands of the colchicine domain in tubulin based on a structure-guided design.
- Bueno O Instituto de Química Médica (IQM,CSIC), Juan de la Cierva 3, 28006, Madrid, Spain.
- Estévez Gallego J Centro de Investigaciones Biológicas (CIB,CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain.
- Martins S Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000, Leuven, Belgium.
- Prota AE Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, 5232, Villigen, Switzerland.
- Gago F Department of Biomedical Sciences (Unidad Asociada IQM,CSIC) and Instituto de Investigación Quimica "Andrés M. del Río" (IQAR), University of Alcalá, Unidad Asociada CSIC, 28805 Alcalá de Henares, Madrid, Spain.
- Gómez-SanJuan A Instituto de Química Médica (IQM,CSIC), Juan de la Cierva 3, 28006, Madrid, Spain.
- Camarasa MJ Instituto de Química Médica (IQM,CSIC), Juan de la Cierva 3, 28006, Madrid, Spain.
- Barasoain I Centro de Investigaciones Biológicas (CIB,CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain.
- Steinmetz MO Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, 5232, Villigen, Switzerland.
- Díaz JF Centro de Investigaciones Biológicas (CIB,CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain.
- Pérez-Pérez MJ Instituto de Química Médica (IQM,CSIC), Juan de la Cierva 3, 28006, Madrid, Spain.
- Liekens S Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000, Leuven, Belgium.
- Priego EM Instituto de Química Médica (IQM,CSIC), Juan de la Cierva 3, 28006, Madrid, Spain. empriego@iqm.csic.es.
- 2018-03-11
Published in:
- Scientific reports. - 2018
Binding Sites
Cell Line
Cell Line, Tumor
Cell Movement
Colchicine
Cyclohexanones
Endothelial Cells
Humans
Ligands
Molecular Docking Simulation
Protein Binding
Tubulin
Tubulin Modulators
English
Microtubule-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 high-resolution 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 K b 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.
- Language
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- English
- Open access status
- gold
- Identifiers
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- DOI 10.1038/s41598-018-22382-x
- PMID 29523799
- Persistent URL
- https://sonar.ch/global/documents/296033
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