Acute myeloid leukemia and myelodysplastic syndromes are incurable hematologic neoplasms in which the angiopoietin-1/Tie-2 pathway is over-activated. Pexmetinib is a small molecular, orally bioavailable inhibitor of the angiopoietin-1 receptor Tie-2 and the pro-inflammatory kinase p38 MAPK. The IC50 values of pexmetinib against Tie-2, p38 MAPK α and β were 1, 35, and 36 nM, respectively. Pexmetinib also inhibited phospho-Tie-2 and phospho-p38 in HEK-Tie2 cells with IC50 values of 16 and 1 nM, respectively. It was predicted that the plasma concentrations of pexmetinib to achieve 50% inhibition for phospho-Tie-2 and phospho-p38 in human blood samples were 2282 and 172 nM, respectively. In TNF-α-treated leukemic KG1 cells, pexmetinib at 10 nM completely abrogated TNF-α-induced activation of p38 MAPK, MAPKAPK2 and EIF4E. In primary CD34+ stem cells, pexmetinib at 0.1 μM significantly reversed the myelosuppressive effects induced by TNF-α[3].
Mechanism: Pexmetinib is a type 2 kinase inhibitor that binds both Tie-2 and p38 MAPK in the “DFG-out” conformation[3].
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