Discovery of a highly selective FLT3 inhibitor with specific proliferation inhibition against AML cells harboring FLT3-ITD mutation

Abstract

FLT3 is often over-expressed in AML, and FLT3 mutants, especially FLT-ITD, are closely related to the poor prognosis in AML patients. Thus, FLT3 has become an attractive target for AML therapy. A series of FLT3 inhibitors have been evaluated in various clinical trials, one of which was approved for AML. However, current FLT3 inhibitors still faced the challenges of kinase selectivity and drug resistance due to concurrent FLT3-ITD-TKD mutations. In this work, a new FLT3 inhibitor (compound 1) with simple structure was discovered through virtually screening an in-house molecule database which contains numerous compounds with kinase-inhibition activity. Compound 1 was identified with potent inhibitory activity against several FLT3 mutants and high FLT3 selectivity over other kinases. Moreover, its anti-growth effects on tumor cells in vitro were dependent on the expression of FLT3-ITD, and it showed little cytotoxicity to MV4-11 and human normal cells. Mechanism studies illustrated that compound 1 blocked FLT3 pathway, caused cell cycle arrest and induced apoptosis in MV4-11 cells. Finally, the binding mode of compound 1 was studied by molecular dynamics simulations, which provides insights into key residues involved in intermolecular binding and further structural optimization strategy. Compound 1 can thus serve as a good starting point for the research on FLT3 inhibitors towards the kinase selectivity and potential to overcome drug resistance.