Background:

KW 2449 is a multikinase inhibitor of FLT3, ABL, ABL-T315I, and Aurora kinase with IC50 values of 6.6nM, 14nM, 4nM and 48nM, respectively [1].

KW-2449 is a potent kinase inhibitor against FLT3, ABL, T315I-mutant ABL (ABL-T315I) tyrosine kinases as well as Aurora kinase. In vitro assay shows KW-2449 has the potency of growth inhibition with different mechanisms. In leukemia cells with FLT3 mutations, KW-2449 down-regulates phosphorylated-FLT3/STAT5, induces G1 arrest and apoptosis. KW-2449 also inhibits tumor growth in FLT3-mutated xenograft model. While in leukemia cells with wild-type FLT3, KW-2449 reduces phosphorylated histone H3, induces G2/M arrest and apoptosis. However, it is reported that the AML patients treated with LT3 inhibitors, such as KW-2449, have only partial FLT3 inhibition in vivo. And the plasma level of FL (the ligand of FLT3) appears to rise after chemotherapy, which impeding the efficacy of the FLT3 inhibitors [1, 2].

参考文献:
[1] Shiotsu Y, Kiyoi H, Ishikawa Y, Tanizaki R, Shimizu M, Umehara H, Ishii K, Mori Y, Ozeki K, Minami Y, Abe A, Maeda H, Akiyama T, Kanda Y, Sato Y, Akinaga S, Naoe T. KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation. Blood. 2009 Aug 20;114(8):1607-17.
[2] Sato T, Yang X, Knapper S, White P, Smith BD, Galkin S, Small D, Burnett A, Levis M. FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo. Blood. 2011 Mar 24;117(12):3286-93.