Design, synthesis, and biological evaluation of 4-(2-fluorophenoxy)pyridine derivatives as novel FLT3-ITD inhibitors

Abstract

FMS-like tyrosine kinase 3 (FLT3) is an ideal drug target for the treatment of acute myeloid leukemia (AML). Although several FLT3 inhibitors have been approved or evaluated in clinical trials, selectivity over c-Kit kinase and FLT3 WT remains a major challenge. Herein, we report a series of 4-(2-fluorophenoxy)pyridine derivatives with potent inhibitory activities against FLT3 internal tandem duplication (FLT3-ITD). The representative compound 13v inhibited FLT3-ITD kinase and isogenic BaF₃-FLT3-ITD cells with nanomolar IC₅₀ values and achieved selectivity over c-Kit (>53-fold) and FLT WT (19-fold) in transformed BaF₃ cells. In addition, compound 13v displayed excellent selectivity against FLT3-ITD driven AML cells compared to other leukemia cells, solid tumors, and normal peripheral blood mononuclear cells. Mechanistic studies revealed that 13v disrupted FLT3 signal transduction and induced G₀/G₁ cell cycle arrest and apoptosis. Moreover, it also showed good developmental profiles in ADME assays. In in vivo studies, 13v demonstrated desirable pharmacokinetic (PK) profiles and sufficient tumor growth inhibition in a MOLM-13 xenograft model. Taken together, 13v may represent a starting point for the development of improved FLT3-ITD inhibitors.