IRC-083927 is a new tubulin binder that inhibits growth of human tumor cells resistant to standard tubulin-binding agents.
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.
Liberatore
Anne-Marie
AM
IPSEN Research Laboratories, Institut Henri Beaufour, 5 Avenue du Canada, Les Ulis, France.
Coulomb
Hélène
H
Pons
Dominique
D
Dutruel
Olivier
O
Kasprzyk
Philip G
PG
Carlson
Mark
M
Nelson
Ann Savola
AS
Newman
Simon P
SP
Stengel
Chloe
C
Auvray
Pierrïck
P
Hesry
Vincent
V
Foll
Béatrice
B
Narboux
Nadine
N
Morlais
Delphine
D
Le Moing
Mélissa
M
Bernetiere
Sonia
S
Dellile
Raphael
R
Camara
Jose
J
Ferrandis
Eric
E
Bigg
Dennis C
DC
Prévost
Grégoire P
GP
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*
D000970:Antineoplastic Agents; D007093:Imidazoles; C532367:N-(2-fluoro-4-(4-(2-(phenoxymethyl)-1H-imidazol-4-yl)phenoxy)phenyl)sulfamide; D013449:Sulfonamides; D014404:Tubulin