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KW 2449 is a multikinase inhibitor of FLT3, ABL, ABL-T315I, and Aurora kinase. KW 2449 displays potent inhibition of growth effects on leukemia cells with FLT3 mutations via inhibition of the FLT3 kinase, resulting in the down-regulation of phosphorylated-FLT3/STAT5, G1 arrest, and apoptosis. KW 2449 induces the reduction of phosphorylated histone H3, G2/M arrest, and apoptosis in FLT3 wild-type human leukemia. KW 2449 contributes to release of the resistance by the simultaneous down-regulation of BCR/ABL and Aurora kinases in imatinib-resistant leukemia. KW 2449 inhibitory activity is not affected by the presence of human plasma protein, such as α1-acid glycoprotein. KW 2449 has potent growth inhibitory activity against various types of leukemia by several mechanisms of action. KW 2449 decreases phosphorylation levels of FLT3 and STAT5 in a dose-dependent manner. KW 2449 is a potent inhibitor of ABL-T315I, which is associated with IM resistance (IC50 of 4 nM). KW-2449 has the potent growth inhibitory activities against not only FLT3/ITD-expressing leukemia cells but also FLT3/KDM-activated and wild-type FLT3-overexpressing leukemia cells. KW 2449 suppresses the phosphorylations of FLT3 (P-FLT3) and its downstream molecule phospho-STAT5 (P-STAT5) in MOLM-13 cells in a dose-dependent manner. KW 2449 can dephosphorylate constitutively active WT-FLT3 kinase but not inhibit the proliferation of leukemia cells if they are not mainly addicted to FLT3 the kinase. KW 2449 mediates cytotoxicity through inhibition of FLT3/ITD. KW 2449 is a direct inhibitor of FLT3 and induces inhibition of its downstream target STAT5. KW 2449 interacts synergistically with HDACIs to induce apoptosis in Ph+ CML cells in a time- and concentration-dependent manner. KW 2449 moderately reduces phosphorylation of histone H3, an indicator of Aurora B activity, in nocodozole-treated K562 cells. |
