Discovery and development of extreme selective inhibitors of the ITD and D835Y mutant FLT3 kinases

Aberrant activation of FMS-like tyrosine receptor kinase 3 (FLT3) is implicated in the pathogenesis of acute myeloid leukemia (AML) in 20–30% of patients. In this study we identified a highly selective (phenylethenyl)quinazoline compound family as novel potent inhibitors of the FLT3-ITD and FLT3-D835Y kinases. Their prominent effects were confirmed by biochemical and cellular proliferation assays followed by mice xenograft studies. Our modelling experiments and the chemical structures of the compounds predict the possibility of covalent inhibition. The most effective compounds triggered apoptosis in FLT3-ITD AML cells but had either weak or no effect in FLT3-independent leukemic and non-leukemic cell lines. Our results strongly suggest that our compounds may become therapeutics in relapsing and refractory AML disease harboring various ITD and tyrosine kinase domain mutations, by their ability to overcome drug resistance. [Display omitted] •Overexpression of FLT3 kinase is particularly common in AML.•Most common mutations of FLT3 are the ITD and the D835 point mutations.•Styrylquinazolines were identified as selective inhibitors of the FLT3-ITD and D835Y kinases.•Covalent binding mode was supported by docking and chemical reactions.•A lead compound effectively blocked tumor growth in xenograft mouse model.