SU11652 Inhibits tyrosine kinase activity of FLT3 and growth of MV-4-11 cells

Background: FLT3-ITD and FLT3-TKD mutations are frequently found in acute myeloid leukemia(AML). This makes tyrosine kinase FLT3 a highly attractive target for therapeutic drugdevelopment. However, effective drugs have not yet emerged. This study is intended toidentify and to characterize new FLT3 inhibitors. Methods: By using the protein substrate GST-FLT3S to analyze kinase activity of recombinant proteinscarrying the catalytic domain of wild type and mutant forms of FLT3, we screened achemical library containing 80 known protein kinase inhibitors. We identified SU11652 as apotent FLT3 inhibitor and further employed FLT3-ITD-positive MV- 4-11 cells to study itseffects on cell growth, apoptosis, cell cycles, and cell signaling. Results: SU11652 strongly inhibited the activity of wild type, D835Y, and D835H mutant forms ofFLT3 with IC50 values of 1.5, 16, and 32 nM, respectively. It effectively blocked the growthof FLT3-ITD -positive MV-4-11 cells at nanomolar concentrations but exhibited much lesseffects on several other cells which do not carry mutations of FLT3. SU11652 inhibitedgrowth of MV-4-11 cells by inducing apoptosis, causing cell cycle arrest, and blockingactivation of the ERK, Akt, and STAT signaling pathways. Conclusion: SU11652 is a potent FLT3 inhibitor which selectively targets FLT3-ITD-positive cells. Itshould serve as a good candidate for development of therapeutic drugs to treat AML.

via Journal of Hematology & Oncology