title: 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.
authors: IPSEN Research Laboratories, Institut Henri Beaufour, 5 Avenue du Canada, Les Ulis, France.
authors: Anne-Marie
authors: AM
authors: Liberatore
authors: Hélène
authors: H
authors: Coulomb
authors: Dominique
authors: D
authors: Pons
authors: Olivier
authors: O
authors: Dutruel
authors: Philip G
authors: PG
authors: Kasprzyk
authors: Mark
authors: M
authors: Carlson
authors: Ann Savola
authors: AS
authors: Nelson
authors: Simon P
authors: SP
authors: Newman
authors: Chloe
authors: C
authors: Stengel
authors: Pierrïck
authors: P
authors: Auvray
authors: Vincent
authors: V
authors: Hesry
authors: Béatrice
authors: B
authors: Foll
authors: Nadine
authors: N
authors: Narboux
authors: Delphine
authors: D
authors: Morlais
authors: Mélissa
authors: M
authors: Le Moing
authors: Sonia
authors: S
authors: Bernetiere
authors: Raphael
authors: R
authors: Dellile
authors: Jose
authors: J
authors: Camara
authors: Eric
authors: E
authors: Ferrandis
authors: Dennis C
authors: DC
authors: Bigg
authors: Grégoire P
authors: GP
authors: Prévost
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D009389:Neovascularization, Pathologic; D013449:Sulfonamides / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014404:Tubulin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; C532367:N-(2-fluoro-4-(4-(2-(phenoxymethyl)-1H-imidazol-4-yl)phenoxy)phenyl)sulfamide; D013449:Sulfonamides; D014404:Tubulin