c-KIT is a tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. c-KIT is a proto-oncogene. Activating or gain of function mutations in c-KIT have been identified in a variety of tumors[3].
Amuvatinib, also termed MP470, is an inhibitor of various mutant c-KIT kinases. The inhibitory IC50s of MP470 against c-KIT(D816V), c-KIT(D816H), c-KIT(V560G), c-KIT(V654A) were 0.95 μM, 0.01 μM, 0.034 μM and 0.127 μM, respectively. The IC50 for MP470 on OVCAR-3 cells proliferation was 0.9 μM[3]. According to another report, the IC50 for MP470 on prostate cancer LNCaP and PC-3 cells were ~4 μM and 8 μM, respectively, when incubated for 4 days. Flow cytometric analysis revealed that 48h treatment of MP470 to LNCaP cells at the concentration of 10 μM induced 28% of apoptosis[4].
In a HT-29 xenograft model, MP470 was i.p. administrated at the doses of 10 or 20 mg/kg at the schedule of 5 times a week for 2 weeks. Both doses significantly inhibited tumor growth. In an A549 xenograft model, MP470 was orally administrated at the doses of 50, 100, or 200 mg/kg, also 5 times a week for 2 weeks. All three doses exhibited anti-tumor activity[3]. In another LNCaP xenograft model, MP470 was i.p. dosed at 50 mg/kg daily for 24 days. This dose in combination with Erlotinib had a marked effect with tumor growth inhibition of 45-65%, while both drugs were of modest activity as a single agent[4].
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