Masitinib mesylate

Biological Activity

Masitinib (AB-1010) mesylate is a potent, orally bioavailable and selective inhibitor of c-Kit, IC50 of 200 nM for human recombinant c-Kit. It also inhibits PDGFRα/β, LynB with IC50 values of 540, 800 and 510 nM. In Ba/F3 cells expressing human wild-type Kit, masitinib inhibits SCF (stem cell factor)-induced cell proliferation with an IC50 of 150 nM, while the IC50 for inhibition of IL-3-stimulated proliferation is at approximately >10 µM. In Ba/F3 cells expressing PDGFRα, masitinib inhibits PDGF-BB-stimulated proliferation and PDGFRα tyrosine phosphorylation with IC50 of 300 nM. Masitinib also causes inhibition of SCF-stimulated tyrosine phosphorylation of human Kit in mastocytoma cell-lines and BMMC.

In vivo, Masitinib inhibits tumour growth and increases the median survival time in Δ27-expressing Ba/F3 tumor models at 30 mg/kg, without cardiotoxicity or genotoxicity.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

Chemical Information

References

[1] Ilaria Marech, et al. Crit Rev Oncol Hematol . Masitinib (AB1010), from canine tumor model to human clinical development: where we are

[2] J Lawrence, et al. Vet Comp Oncol . Masitinib demonstrates anti-proliferative and pro-apoptotic activity in primary and metastatic feline injection-site sarcoma cells

[3] Patrice Dubreuil, et al. PLoS One . Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT