生物活性

• 靶点

  c-Kit IC50:200nM

  PDGFRα IC50:540nM

  PDGFRβ IC50:800nM

• 描述The stem cell factor (SCF) receptor, KIT, also called CD117 or c-KIT receptor, is a member of the type III receptor proteintyrosine kinase family (RTK). This family also includes Flt3, the platelet-derived growth factor (PDGF) receptor, and the receptor for macrophage colony-stimulating factor/colony-stimulating factor-1 (c-Fms). Masitinib mesylate is a novel inhibitor for Kit and PDGFRα/β with IC₅₀ of 200 nM, 540 nM and 800 nM, and has weak inhibition to ABL and c-Fms. In Ba/F3 cells expressing human wildtype KIT, masitinib dose-dependently inhibited SCF-induced cell proliferation with an IC₅₀ of 150 nM. In contrast, the IC₅₀ for inhibition of IL-3-stimulated proliferation occurred at approximately ＞5 mM. Assessment of masitinib's ability to inhibit the FceRI-mediated degranulation of human cord-blood-derived mast cells (CBMC) showed that this compound produced a dose-dependent inhibition of β-hexosaminidase release by IgE-anti IgE activated CBMC after 30 minutes of stimulation. Upon treatment with 1.0 mM of masitinib, migration of SCF-stimulated murine bone marrow mast cell (BMMCs) was inhibited approximately 79.6% (p=0.029) relative to the control, which suggested Masitinib inhibited migration of bone marrow cells. Masitinib dose-dependently inhibited D27 KIT-dependent proliferation of Ba/F3 cells with an IC₅₀ of 5.0 nM, it also caused a parallel reduction in its tyrosine phosphorylation. In the mouse model of tumour growth with D27-expressing Ba/F3 cells, tumour growth stabilised in mice treated with masitinib, whereas placebo treated mice had a mean doubling time of 5 days. A significant difference in average tumour volume was evident after 10 days of treatment (day 29), the placebo group showing an approximate 4-fold increase compared to the masitinib treated group (p=0.016). The administered dose of masitinib did not affect the total body weight of the mice during the course of the study. Furthermore, masitinib increased the median survival time from 30.5 to 42 days (p＜0.001) relative to the control population.