Ilginatinib maleate

Ilginatinib maleate (NS-018 maleate) is a highly active and orally bioavailable JAK2 inhibitor, with an IC 50 of 0.72 nM, 46-, 54-, and 31-fold selectivity for JAK2 over JAK1 ( IC 50 , 33 nM), JAK3 ( IC 50 , 39 nM), and Tyk2 ( IC 50 , 22 nM).

In Vitro

Ilginatinib maleate (NS-018 maleate) is a highly active JAK2 inhibitor, with an IC 50 of 0.72 nM, 46-, 54-, and 31-fold selectivity for JAK2 over JAK1 (IC 50 , 33 nM), JAK3 (IC 50 , 39 nM), and Tyk2 (IC 50 , 22 nM). Ilginatinib maleate also inhibits Src-family kinases, especially SRC and FYN, and weakly inhibits ABL and FLT3 with 45- and 90-fold selectivity for JAK2, respectively. Ilginatinib maleate shows potent inhibitory activity against cell lines JAK2V617F or MPLW515L mutations or the TEL-JAK2 fusion gene (expressing a constitutively activated JAK2) with IC 50 of 11-120 nM, but has only minimal cytotoxicity against most other hematopoietic cell lines that have no constitutively activated JAK2. Ilginatinib maleate (0.5 μM) preferentially suppresses colony-forming unitgranulocyte/macrophage (CFU-GM) formation from myelodysplastic syndrome (MDS)-derived bone marrow mononuclear cells (BMMNCs). Ilginatinib maleate (1 μM) suppresses the phosphorylation of STAT3 (the downstream kinase of JAK2) in CFU-GM-forming cells from MDS patients. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

In Vivo

Ilginatinib maleate (NS-018 maleate) (12.5, 25, 50, 100 mg/kg, p.o.) potently prolongs the survival of mice and reduces splenomegaly in a mouse Ba/F3-JAK2V617F disease model . Ilginatinib maleate (25, 50 mg/kg, p.o.) significantly reduces leukocytosis, hepatosplenomegaly and extramedullary hematopoiesis, improves nutritional status, and prolongs survival in JAK2V617F transgenic mice . MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Cell Assay

Bone marrow mononuclear cells (BMMNCs) from healthy volunteers and myelodysplastic syndrome (MDS) patients are incubated in MethoCult GF H4434 methylcellulose medium containing various hematopoietic cytokines at 1.0 × 10 5 cells/mL with or without NS-018 at 37°C in a humidified atmosphere of 5% CO 2 . Commercially available purified normal human CD34-positive (CD34 + ) BM cells are used as a control. Burst-forming unit-erythroid (BFU-E) and colonyforming unit-granulocyte/macrophage (CFU-GM) colonies are counted under an inverted microscope on day 14 of culture. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

IC50& Target:JAK2 0.72 nM (IC 50 ) Tyk2 22 nM (IC 50 ) JAK1 33 nM (IC 50 ) JAK3 39 nM (IC 50 )