新型FLT3抑制剂LT-171-861抗急性髓系白血病的作用及潜在靶点的发现性研究

急性髓系白血病（AML）是我国发病率最高的白血病，5年生存率仅为25%，而FLT3突变的AML患者约占30%，其临床预后更差、生存率更低。目前应用的FLT3抑制剂体内半衰期较短，易耐药，难以满足治疗需求。LT-171-861是全合成的新型FLT3抑制剂，它在AML治疗中的作用还尚未报道。前期研究发现，LT-171-861能在体内外选择性抑制FLT3-ITD突变AML细胞的生长，克服FL配体升高引起的耐药。另外，LT-171-861对非FLT3突变AML细胞也有一定的活力抑制作用，提示LT-171-861还可能通过其它靶点起到抗AML作用。本项目旨在结合AML临床样本，阐明LT-171-861的抗AML作用，揭示LT-171-861对突变/微环境介导耐药的影响，探索LT-171-861的潜在靶点，验证其在AML中的病理功能，评价LT-171-861的联合方案，为AML靶向治疗提供思路。

Acute myeloid leukemia (AML) is the most prevalent leukemia in China and its 5-year survival rate is only 25%, whereas the AML patients with FLT3 mutation account for about 30%, with worse clinical prognosis and lower survival rate. Currently, FLT3 inhibitor has a short half-life, and it is easy to genreate resistance, which is difficult to meet the needs of treatment. LT-171-861 is a novel FLT3 inhibitor synthesized in our group, and its effect in AML therapy has not been reported. Previous studies have found that LT-171-861 can selectively inhibit the growth of FLT3-ITD mutant AML cells in vitro and in vivo, and overcome the resistance caused by the increase of FL ligand. In addition, LT-171-861 also inhibited the viability of non-FLT3 mutant AML cells, suggesting that LT-171-861 may also possess an anti-AML effect through other targets. This project aims to combine the clinical samples of AML to elucidate the anti-AML effect of LT-171-861, to reveal the impact of LT-171-861 on the mutation/microenvironment-mediated resistance, to explore the potential target of LT-171-861, to verify the pathological function of this target in AML, and finally to evaluate the combination drug therapy of LT-171-861, which will provide new ideas for the targeted therapy of AML.