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.

同时靶向Fms样酪氨酸激酶3（Fms-like tyrosine kinase 3，FLT3）/血管内皮生长因子受体2（vascular endothelial growth factor receptor 2，VEGFR2）/组蛋白去乙酰化酶（histone deacetylase，HDAC），是一种针对急性髓系白血病的新型且极具潜力的治疗策略。本研究中，我们将索拉非尼（sorafenib）与SAHA（伏立诺他，vorinostat）的关键药效团进行杂交，并开展构效关系研究，最终筛选得到两个先导化合物26与32，二者可在纳摩尔浓度范围内强效抑制FLT3、VEGFR2及HDAC的活性。细胞水平评价结果显示，化合物26与32对包括MV4-11、MOLM-13在内的多株白血病细胞均展现出强效的增殖抑制活性。蛋白质免疫印迹（Western blotting）分析进一步表明，化合物26与32可呈剂量依赖性地抑制FLT3、信号转导与转录激活因子3（signal transducer and activator of transcription 3，STAT3）及细胞外调节蛋白激酶1/2（extracellular regulated protein kinases 1/2，ERK1/2）的磷酸化水平，并提升组蛋白H3的乙酰化程度，证实其可有效靶向FLT3、VEGFR2与HDAC。基于其良好的药代动力学特性，化合物26在MV4-11异种移植瘤模型中展现出显著的抗肿瘤疗效。此外，在Ba/F3-FLT3-ITD-N701K异种移植瘤模型中，其疗效优于米哚妥林（midostaurin）与吉列替尼（gilteritinib）。