Masitinib (AB1010), a Potent and Selective Tyrosine Kinase Inhibitor Targeting KIT

Abstract : Background: The stem cell factor receptor, KIT, is a target for the treatment of cancer, mastocytosis, and inflammatory diseases. Here, we characterise the in vitro and in vivo profiles of masitinib (AB1010), a novel phenylaminothiazole-type tyrosine kinase inhibitor that targets KIT. Methodology/Principal Findings: In vitro, masitinib had greater activity and selectivity against KIT than imatinib, inhibiting recombinant human wild-type KIT with an half inhibitory concentration (IC50) of 200 ± 40 nM and blocking stem cell factor-induced proliferation and KIT tyrosine phosphorylation with an IC50 of 150 ± 80 nM in Ba/F3 cells expressing human or mouse wild-type KIT. Masitinib also potently inhibited recombinant PDGFR and the intracellular kinase Lyn, and to a lesser extent, fibroblast growth factor receptor 3. In contrast, masitinib demonstrated weak inhibition of ABL and c-Fms and was inactive against a variety of other tyrosine and serine/threonine kinases. This highly selective nature of masitinib suggests that it will exhibit a better safety profile than other tyrosine kinase inhibitors; indeed, masitinib-induced cardiotoxicity or genotoxicity has not been observed in animal studies. Molecular modelling and kinetic analysis suggest a different mode of binding than imatinib, and masitinib more strongly inhibited degranulation, cytokine production, and bone marrow mast cell migration than imatinib. Furthermore, masitinib potently inhibited human and murine KIT with activating mutations in the juxtamembrane domain. In vivo, masitinib blocked tumour growth in mice with subcutaneous grafts of Ba/F3 cells expressing a juxtamembrane KIT mutant. Conclusions: Masitinib is a potent and selective tyrosine kinase inhibitor targeting KIT that is active, orally bioavailable in vivo, and has low toxicity
Liste complète des métadonnées

Littérature citée [33 références]  Voir  Masquer  Télécharger

http://www.hal.inserm.fr/inserm-00423392
Contributeur : Patrice Dubreuil <>
Soumis le : vendredi 9 octobre 2009 - 16:56:36
Dernière modification le : mercredi 20 juin 2018 - 11:54:02
Document(s) archivé(s) le : mercredi 16 juin 2010 - 00:34:58

Fichier

masitinib.pdf
Fichiers éditeurs autorisés sur une archive ouverte

Identifiants

Collections

Citation

Patrice Dubreuil, Sébastien Letard, Marco Ciufolini, Laurent Gros, Martine Humbert, et al.. Masitinib (AB1010), a Potent and Selective Tyrosine Kinase Inhibitor Targeting KIT. PLoS ONE, Public Library of Science, 2009, 4 (9), pp.e7258. 〈10.1371/journal.pone.0007258〉. 〈inserm-00423392〉

Partager

Métriques

Consultations de la notice

738

Téléchargements de fichiers

556