6GJ4

Tubulin-6j complex

Summary for 6GJ4

• Entry DOI: 10.2210/pdb6gj4/pdb
• Descriptor: Tubulin alpha-1B chain, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, ... (12 entities in total)
• Functional Keywords: cell cycle, tubulin fold, cytoskeleton, microtubule
• Biological source: Rattus norvegicus (Norway rat); More
• Total number of polymer chains: 6
• Total formula weight: 265303.10

Authors

Brindisi, M.,Ulivieri, C.,Alfano, G.,Gemma, S.,Balaguer, F.d.A.,Khan, T.,Grillo, A.,Chemi, G.,Menchon, G.,Prota, A.E.,Olieric, N.,Agell, D.L.,Barasoain, I.,Diaz, J.F.,Nebbioso, A.,Conte, M.R.,Lopresti, L.,Magnano, S.,Amet, R.,Kinsella, P.,Zisterer, D.M.,Ibrahim, O.,O'Sullivan, J.,Morbidelli, L.,Spaccapelo, R.,Baldari, C.,Butini, S.,Novellino, E.,Campiani, G.,Altucci, L.,Steinmetz, M.O.,Brogi, S. (deposition date: 2018-05-16, release date: 2018-12-05, Last modification date: 2024-01-17)

Primary citation

Brindisi, M.,Ulivieri, C.,Alfano, G.,Gemma, S.,de Asis Balaguer, F.,Khan, T.,Grillo, A.,Chemi, G.,Menchon, G.,Prota, A.E.,Olieric, N.,Lucena-Agell, D.,Barasoain, I.,Diaz, J.F.,Nebbioso, A.,Conte, M.,Lopresti, L.,Magnano, S.,Amet, R.,Kinsella, P.,Zisterer, D.M.,Ibrahim, O.,O'Sullivan, J.,Morbidelli, L.,Spaccapelo, R.,Baldari, C.,Butini, S.,Novellino, E.,Campiani, G.,Altucci, L.,Steinmetz, M.O.,Brogi, S.
Structure-activity relationships, biological evaluation and structural studies of novel pyrrolonaphthoxazepines as antitumor agents.
Eur J Med Chem, 162:290-320, 2018

PubMed Abstract: Microtubule-targeting agents (MTAs) are a class of clinically successful anti-cancer drugs. The emergence of multidrug resistance to MTAs imposes the need for developing new MTAs endowed with diverse mechanistic properties. Benzoxazepines were recently identified as a novel class of MTAs. These anticancer agents were thoroughly characterized for their antitumor activity, although, their exact mechanism of action remained elusive. Combining chemical, biochemical, cellular, bioinformatics and structural efforts we developed improved pyrrolonaphthoxazepines antitumor agents and their mode of action at the molecular level was elucidated. Compound 6j, one of the most potent analogues, was confirmed by X-ray as a colchicine-site MTA. A comprehensive structural investigation was performed for a complete elucidation of the structure-activity relationships. Selected pyrrolonaphthoxazepines were evaluated for their effects on cell cycle, apoptosis and differentiation in a variety of cancer cells, including multidrug resistant cell lines. Our results define compound 6j as a potentially useful optimized hit for the development of effective compounds for treating drug-resistant tumors.

PubMed: 30448418
DOI: 10.1016/j.ejmech.2018.11.004

Experimental method

X-RAY DIFFRACTION (2.4 Å)