基于酪氨酸激酶FLT3D835突变抑制剂SU11652的作用机制和在AML靶向治疗中有效性的研究

急性髓系白血病（AML）是起源于造血干细胞的恶性血液病，目前主要的治疗方法是标准化疗法，但这种疗法对多数患者的效果并不理想，而且有着多种弊端。随着生物医学的发展和对AML发病机制的深入研究，以酪氨酸激酶FLT3为靶点的靶向治疗成为最有希望替代标准化疗法的治疗方法之一。然而，在应用现有FLT3抑制剂的治疗过程中，绝大多数患者会出现FLT3 D835耐药突变从而导致FLT3抑制剂失去疗效。我们在前期工作中筛选到了FLT3和FLT3 D835突变的新型抑制剂SU11652，本课题将在分子水平、细胞水平和动物水平上深入研究SU11652对FLT3 D835突变抑制作用的有效性和分子机制，为以FLT3 D835突变为靶点的AML药物开发和精准医疗提供理论依据。

Acute myeloid leukemia (AML) is a malignant hematopoietic disorder. The current treatment method is the standard chemotherapy, which is not effective in most patients. With the development of modern biomedical sciences and the understanding of AML pathogenesis, the targeted therapy which targets tyrosine kinase FLT3 has become one of the most important treatment method for AML in the future. However, duiring the clinical application, AML patients became resistant to existing FLT3 inhibitors due to FLT3 D835 point mutations expressed in the leukemia blast cells, which has become a major problem for the clinical application of FLT3 inhibitors in AML therapy. To solve this problem, we screened a compound named SU11652,an unique inhibitor which can target both FLT3 and FLT3 D835 mutants effectively. In this study, we will further characterize the novel inhibitor SU11652 to investigate its effectiveness and the moleclular mechanism to treat FLT3 D835 mutants by performing biochmcial, cell-based, and animal-based assays. This study should provide a theoratical basis for the drugs development and precision medicine in AML therapy besed on targeting FLT3 D835 mutation in the future.