Discovery of pyridine-based derivatives as FLT3 inhibitors for the treatment of acute myeloid leukemia.

FMS-like tyrosine receptor kinase 3 (FLT3) mutations, the most common genetic alterations found in acute myeloid leukemia (AML) patients, have been pursued as an ideal drug discovery target for the AML therapy. Taking compound 2 as lead, a series of pyridine derivatives bearing 1,2,3-triazole moiety were rationally designed and synthesized. The bioassays confirmed that these derivatives exerted potent antileukemia effects, and compound 12y was found to be the most potent one. 12y displayed double-digital nanomolar inhibitory activities against FLT3-ITD and FLT3-ITD driven human AML MOLM-13 cells as well as high selectivity over FLT3-ITD non-addicted cell lines. In addition, kinase profiling versus over 51 kinases demonstrated that 12y was potent against FLT3-ITD and VEGFR2. Moreover, treatment of MOLM-13 cells with 12y resulted in downregulated phosphorylation levels of FLT3 and STAT5, as well as cell cycle arrest and apoptosis. With the acceptable oral bioavailability of 19.2 % in SD rats, 12y prolonged the survival rate of NSG mice dose-dependently in MOLM-13 inoculated xenograft model without obvious toxicity. Overall, this study might provide a new insight for the development of novel FLT3 inhibitors.