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.