Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT.
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.


RESULTS
In vitro, masitinib had greater activity and selectivity against KIT than imatinib, inhibiting recombinant human wild-type KIT with an half inhibitory concentration (IC(50)) of 200+/-40 nM and blocking stem cell factor-induced proliferation and KIT tyrosine phosphorylation with an IC(50) 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.
Dubreuil
Patrice
P
INSERM, U891, Centre de Recherche en Cancérologie de Marseille, Signalisation, Hematopoiesis and Mechanisms of Oncogenesis, Centre de référence des mastocytoses, Marseille, France. patrice.dubreuil@inserm.fr
Letard
Sébastien
S
Ciufolini
Marco
M
Gros
Laurent
L
Humbert
Martine
M
Castéran
Nathalie
N
Borge
Laurence
L
Hajem
Bérengère
B
Lermet
Anne
A
Sippl
Wolfgang
W
Voisset
Edwige
E
Arock
Michel
M
Auclair
Christian
C
Leventhal
Phillip S
PS
Mansfield
Colin D
CD
Moussy
Alain
A
Hermine
Olivier
O
D000818:Animals; D001549:Benzamides; D001854:Bone Marrow Cells / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009154:Mutation; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D011725:Pyridines; D011994:Recombinant Proteins / Q000737:chemistry; D013844:Thiazoles / Q000494:pharmacology
D001549:Benzamides; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011994:Recombinant Proteins; D013844:Thiazoles; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; C526575:masitinib