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IRC-083927 is a new tubulin binder that inhibits growth of human tumor cells resistant to standard tubulin-binding agents.

Abstract
Tubulin is a validated target for antitumor drugs. However, the effectiveness of these microtubule-interacting agents is limited by the fact that they are substrates for drug efflux pumps (P-glycoprotein) and/or by the acquisition of point mutations in tubulin residues important for drug-tubulin binding. To bypass these resistance systems, we have identified and characterized a novel synthetic imidazole derivative IRC-083927, which inhibits the tubulin polymerization by a binding to the colchicine site. IRC-083927 inhibits in vitro cell growth of human cancer cell lines in the low nanomolar range. More interesting, it remains highly active against cell lines resistant to microtubule-interacting agents (taxanes, Vinca alkaloids, or epothilones). Such resistances are due to the presence of efflux pumps (NCI-H69/LX4 resistant to navelbine and paclitaxel) and/or the presence of mutations on beta-tubulin and on alpha-tubulin and beta-tubulin (A549.EpoB40/A549.EpoB480 resistant to epothilone B or paclitaxel). IRC-083927 displayed cell cycle arrest in G(2)-M phase in tumor cells, including in the drug-resistant cells. In addition, IRC-083927 inhibited endothelial cell proliferation in vitro and vessel formation in the low nanomolar range supporting an antiangiogenic behavior. Finally, chronic oral treatment with IRC-083927 (5 mg/kg) inhibits the growth of two human tumor xenografts in nude mice (C33-A, human cervical cancer and MDA-MB-231, human hormone-independent breast cancer). Together, the antitumor effects induced by IRC-083927 on tumor models resistant to tubulin agents support further investigations to fully evaluate its potential for the treatment of advanced cancers, particularly those resistant to current clinically available drugs.
AuthorsAnne-Marie Liberatore, Hélène Coulomb, Dominique Pons, Olivier Dutruel, Philip G Kasprzyk, Mark Carlson, Ann Savola Nelson, Simon P Newman, Chloe Stengel, Pierrïck Auvray, Vincent Hesry, Béatrice Foll, Nadine Narboux, Delphine Morlais, Mélissa Le Moing, Sonia Bernetiere, Raphael Dellile, Jose Camara, Eric Ferrandis, Dennis C Bigg, Grégoire P Prévost
JournalMolecular cancer therapeutics (Mol Cancer Ther) Vol. 7 Issue 8 Pg. 2426-34 (Aug 2008) ISSN: 1535-7163 [Print] United States
PMID18723488 (Publication Type: Journal Article)
Chemical References
  • Antineoplastic Agents
  • Imidazoles
  • N-(2-fluoro-4-(4-(2-(phenoxymethyl)-1H-imidazol-4-yl)phenoxy)phenyl)sulfamide
  • Sulfonamides
  • Tubulin
Topics
  • Animals
  • Antineoplastic Agents (pharmacokinetics, pharmacology)
  • Biological Availability
  • Cell Cycle (drug effects)
  • Cell Division (drug effects)
  • Drug Resistance, Neoplasm
  • Humans
  • Imidazoles (pharmacology)
  • Mice
  • Neovascularization, Pathologic
  • Sulfonamides (pharmacology)
  • Transplantation, Heterologous
  • Tubulin (metabolism)

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