5JVD

Tubulin-TUB092 complex

Summary for 5JVD

• Entry DOI: 10.2210/pdb5jvd/pdb
• Descriptor: Tubulin alpha-1B chain, GUANOSINE-5'-DIPHOSPHATE, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (13 entities in total)
• Functional Keywords: cell cycle, tubulin fold, cytoskeleton, microtubule
• Biological source: Rattus norvegicus (Rat); More
• Cellular location: Cytoplasm, cytoskeleton: P81947 Q6B856; Golgi apparatus : P63043
• Total number of polymer chains: 6
• Total formula weight: 265507.33

Authors

Canela, M.-D.,Noppen, S.,Bueno, O.,Prota, A.E.,Bargsten, K.,Saez-Calvo, G.,Jimeno, M.-L.,Benkheil, M.,Ribatti, D.,Velazquez, S.,Camarasa, M.-J.,Diaz, J.F.,Steinmetz, M.O.,Priego, E.-M.,Perez-Perez, M.-J.,Liekens, S. (deposition date: 2016-05-11, release date: 2016-06-08, Last modification date: 2024-05-08)

Primary citation

Canela, M.D.,Noppen, S.,Bueno, O.,Prota, A.E.,Bargsten, K.,Saez-Calvo, G.,Jimeno, M.L.,Benkheil, M.,Ribatti, D.,Velazquez, S.,Camarasa, M.J.,Diaz, J.F.,Steinmetz, M.O.,Priego, E.M.,Perez-Perez, M.J.,Liekens, S.
Antivascular and antitumor properties of the tubulin-binding chalcone TUB091.
Oncotarget, 8:14325-14342, 2017

PubMed 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.

PubMed: 27224920
DOI: 10.18632/oncotarget.9527

Experimental method

X-RAY DIFFRACTION (2.393 Å)