Design, Synthesis, and Biological Evaluation of Novel Fms-Like Tyrosine Kinase 3/VEGFR2/Histone Deacetylase Inhibitors for the Treatment of Acute Myeloid Leukemia
Hua Tian, Yichen Liu, Songwen Lin, Jialing Deng, Qinghua Zhang, Feng Hao, Yao Tang, Tianning Xiong, Kehui Zhang, Ge Shi, Lijun Luo, Shouguo Peng, Sheng Li, Ming Ji, Heng Xu
Abstract
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.