Design, Synthesis, and Biological Evaluation of Novel Fms-Like Tyrosine Kinase 3/VEGFR2/Histone Deacetylase Inhibitors for the Treatment of Acute Myeloid Leukemia

The concurrent targeting of Fms-like tyrosine kinase
3 (FLT3)/VEGFR2/Histone
deacetylase (HDAC) represents a novel and promising therapeutic strategy
for acute myeloid leukemia. In this work, we hybridized essential
pharmacophores from sorafenib and SAHA (vorinostat) and then conducted
structure–activity relationship studies to identify two lead
compounds 26 and 32 that potently inhibit
FLT3, VEGFR2, and HDAC in a nanomolar range. In cell evaluation, compounds 26 and 32 exhibited potent proliferative activities
against a panel of leukemia cells including MV4-11 and MOLM-13. Western
blotting analysis also showed that compounds 26 and 32 suppressed the phosphorylation of FLT3, STAT3, and ERK1/2
and increased histone H3 acetylation in a dose-dependent manner, indicating
the effective inhibition of FLT3, VEGFR2, and HDAC. Supported by its
pharmacokinetic properties, compound 26 showed remarkable
anticancer efficacy in a MV4-11 xenograft model. Additionally, it
demonstrated superior efficacy compared to midostaurin and gilteritinib
in the Ba/F3-FLT3-ITD-N701K xenograft model.