Antivascular and antitumor properties of the tubulin-binding chalcone TUB091.

// Maria-Dolores Canela 1 , Sam Noppen 2 , Oskia Bueno 1 , Andrea E. Prota 3 , Katja Bargsten 3 , Gonzalo Saez-Calvo 4 , Maria-Luisa Jimeno 5 , Mohammed Benkheil 2 , Domenico Ribatti 6 , Sonsoles Velazquez 1 , Maria-Jose Camarasa 1 , J. Fernando Diaz 4 , Michel O. Steinmetz 3 , Eva-Maria Priego 1 , Maria-Jesus Perez-Perez 1 , Sandra Liekens 2 1 Instituto de Quimica Medica (IQM-CSIC), Madrid, Spain 2 KU Leuven – University of Leuven, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Leuven, Belgium 3 Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut, Villigen, Switzerland 4 Centro de Investigaciones Biologicas (CIB-CSIC), Madrid, Spain 5 Centro de Quimica Organica Lora-Tamayo (CENQUIOR-CSIC), Madrid, Spain 6 Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, National Cancer Institute “Giavanni Paolo II”, Bari, Italy Correspondence to: Sandra Liekens, email: sandra.liekens@kuleuven.be Maria-Jesus Perez-Perez, email: mjperez@iqm.csic.es Keywords: cancer, drug research, tubulin, vascular-disrupting Received: January 15, 2016      Accepted: May 01, 2016      Published: May 20, 2016 ABSTRACT We investigated the microtubule-destabilizing, vascular-targeting, anti-tumor and anti-metastatic activities of a new series of chalcones, whose prototype compound is (E)-3-(3’’-amino-4’’-methoxyphenyl)-1-(5’-methoxy-3’,4’-methylendioxyphenyl)-2-methylprop-2-en-1-one (TUB091). X-ray crystallography showed that these chalcones bind to the colchicine site of tubulin and therefore prevent the curved-to-straight structural transition of tubulin, which is required for microtubule formation. Accordingly, TUB091 inhibited cancer and endothelial cell growth, induced G2/M phase arrest and apoptosis at 1-10 nM. In addition, TUB091 displayed vascular disrupting effects in vitro and in the chicken chorioallantoic membrane (CAM) assay at low nanomolar concentrations. A water-soluble L-Lys-L-Pro derivative of TUB091 (i.e. TUB099) showed potent antitumor activity in melanoma and breast cancer xenograft models by causing rapid intratumoral vascular shutdown and massive tumor necrosis. TUB099 also displayed anti-metastatic activity similar to that of combretastatin A4-phosphate. Our data indicate that this novel class of chalcones represents interesting lead molecules for the design of vascular disrupting agents (VDAs). Moreover, we provide evidence that our prodrug approach may be valuable for the development of anti-cancer drugs.