Gilteritinib (ASP2215) effectively inhibits FLT3, leukocyte tyrosine kinase (LTK), anaplastic lymphoma kinase (ALK), and AXL kinases in 78 tested tyrosine kinases, achieving over 50% inhibition at 1 nM. Its IC50 for FLT3 is exceptionally low at 0.29 nM, making it roughly 800 times more potent against FLT3 than c-KIT[1]. Gilteritinib inhibits the activity of 8 of the 78 tested kinases by >50% at concentrations of 1 nM (Flt3, LTK, ALK, and Ax1) or 5 nM (TrkA, ROS, RET, and Mer). Its IC50s are 0.29 nM and 0.73 nM, respectively. Gilteritinib inhibits Flt3 with an IC50 approximately 800-fold higher than the concentration required to inhibit c-kit (230 NM). The antiproliferative activity of Gilteritinib is evaluated by MV4-11 and MOLM-13 cells endogenously expressing Flt3-ITD. After 5 days of treatment, the IC50 of gitlitinib for MV4-11 and MOLM-13 cells is 0.92 nM (95%CI: 0.23-3.6 nM) and 2.9 nM (95%CI: 1.4-5.8 nM), respectively. Growth inhibition of MV4-11 cells is accompanied by inhibition of Flt3 phosphorylation. The phosphorylation levels of Flt3 were 57%, 8%, and 1% after 2 h of Gilteritinib at 0.1 nM, 1 nM, and 10 nM compared to vehicle controls, respectively. In addition, doses as low as 0.1 nM or 1 nM inhibit phosphorylated ERK, STAT5, and AKT, all of which are downstream targets for Flt3 activation. To investigate the effect of Gilteritinib on Ax1 inhibition, MV4-11 cells expressing exogenous Ax1 are treated with Gilteritinib. Gilteritinib treatment reduces phosphorylated Axl levels by 38%, 29%, and 22%, respectively, at 4 h at concentrations of 1 nM, 10 nM, and 100 nM[2].
体内研究
In mice with MV4-11 xenografts, oral Gilteritinib (ASP2215) administration at 10 mg/kg for 4 days results in tumor concentrations more than 20 times higher than in plasma. A 28-day treatment with Gilteritinib shows a dose-dependent reduction in MV4-11 tumor growth, achieving complete tumor regression at doses above 6 mg/kg. Additionally, Gilteritinib reduces the tumor load in the bone marrow and extends the survival of mice that received intravenous transplants of MV4-11 cells[1].
体外研究
Gilteritinib (ASP2215) effectively inhibits FLT3, leukocyte tyrosine kinase (LTK), anaplastic lymphoma kinase (ALK), and AXL kinases in 78 tested tyrosine kinases, achieving over 50% inhibition at 1 nM. Its IC50 for FLT3 is exceptionally low at 0.29 nM, making it roughly 800 times more potent against FLT3 than c-KIT[1].
Gilteritinib inhibits the activity of 8 of the 78 tested kinases by >50% at concentrations of 1 nM (Flt3, LTK, ALK, and Ax1) or 5 nM (TrkA, ROS, RET, and Mer). Its IC50s are 0.29 nM and 0.73 nM, respectively. Gilteritinib inhibits Flt3 with an IC50 approximately 800-fold higher than the concentration required to inhibit c-kit (230 NM). The antiproliferative activity of Gilteritinib is evaluated by MV4-11 and MOLM-13 cells endogenously expressing Flt3-ITD. After 5 days of treatment, the IC50 of gitlitinib for MV4-11 and MOLM-13 cells is 0.92 nM (95%CI: 0.23-3.6 nM) and 2.9 nM (95%CI: 1.4-5.8 nM), respectively. Growth inhibition of MV4-11 cells is accompanied by inhibition of Flt3 phosphorylation. The phosphorylation levels of Flt3 were 57%, 8%, and 1% after 2 h of Gilteritinib at 0.1 nM, 1 nM, and 10 nM compared to vehicle controls, respectively. In addition, doses as low as 0.1 nM or 1 nM inhibit phosphorylated ERK, STAT5, and AKT, all of which are downstream targets for Flt3 activation. To investigate the effect of Gilteritinib on Ax1 inhibition, MV4-11 cells expressing exogenous Ax1 are treated with Gilteritinib. Gilteritinib treatment reduces phosphorylated Axl levels by 38%, 29%, and 22%, respectively, at 4 h at concentrations of 1 nM, 10 nM, and 100 nM[2].
作用机制
Gilteritinib binds to FLT3 at the ATP-binding site.[2]
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