基于FLT3新型结构模型筛选优化特异性抑制小分子化合物及其抗急性髓系白血病的活性研究

急性髓系白血病（AML）约占成人急性白血病的80%。除AML-M3因靶向治疗的引入显著提高治愈率外，其余类型AML的治疗进展颇缓，五年生存率不足40%。FLT3基因在成人AML中突变率高达30%，其突变体在不依赖配体情况下自身持续磷酸化，异常激活信号通路，参与AML的发生发展。FLT3作为AML最具潜力的治疗靶点受到国内外学者广泛研究，FLT3小分子抑制剂尽管取得一定研究进展，但由于药物设计原因均存在特异性差、脱靶后毒副作用或继发耐药突变等问题。为克服以上问题，本项目组前期通过分子动力学模拟发现FLT3除已报道的自我抑制及活化状态外还普遍存在配体非依赖性中间非活化状态。我们将利用新发现的FLT3中间非活化状态结构模型，以及自我抑制、活化结构状态模型，寻找新的小分子结合位点，通过计算机筛选、优化其专一抑制化合物，并在生化、细胞、动物模型水平上验证其抗FLT3突变型AML的活性及特异性。

Acute myeloid leukemia (AML) accounts for 80% of all adult acute leukemia population, however, until now, the 5-year overall survival rate is less than 40% (excluding AML-M3, because it is almost completely cured by targeted therapy). FLT3 (FMS-like tyrosine kinase 3) is one of the most frequently mutated genes (~ 30%) in AML patients. FLT3 mutated proteins acquire constitutive activation of the FLT3 receptor tyrosine kinase capacity independent of ligand and lead to abnormal activities of downstream pathways, which result in cell proliferation and leukemogenesis. As one of the most attractive therapeutic targets in the treatment of AML, FLT3 inhibitors were widely studied and designed by scientists. Although most of the identified inhibitors showed positive activities against FLT3 mutated AML, they also keep defects like poor specificity, toxic and side effects and secondary drug resistant mutations. Our preliminary molecular dynamics studies revealed a ligand independent intermediated inactive status of FLT3 which is different from the known auto-inhibition status and active status. Next, we plan to take advantage of the the active and intermediated statuses of the wide type and mutated FLT3 proteins, the auto-inhibition status of FLT3 wide type protein to search for small molecular binding sites. Also, we would virtually screening and optimizing potent FLT3 small molecular inhibitors and then validating their anti AML activity and potency from biochemistry level, cellular level and animal model level.