基于结构的新型选择性FLT3共价抑制剂的设计、合成及其对（复发性及预后不良）急性髓性白血病的生物活性研究

FLT3过表达导致急性髓性白血病（AML），突变会诱发耐药，共价抑制剂有望解决耐药。本项目前期以Linifanib为模版，得到的II型不可逆共价抑制剂S35对wt-FLT3（IC50=1.4nM）、FLT3-ITD（IC50=1.2nM）、FLT3-D835Y（IC50=1.7nM）活性强，其Michael受体与wt-FLT3中Cys807形成共价键。但对FLT3-ITD-F691L（IC50=16.1nM）活性弱，原因是S35苯环与wt-FLT3门控691位苯丙胺酸形成pi-pi堆积作用，二次突变后苯丙胺酸变成亮氨酸pi-pi作用消失、分子构象变化、共价键消失而导致耐药。本项目将采用骨架跃迁、生物电子等排等方法，对S35进行修饰，调整Michael受体与连接链分子构象，避免pi-pi堆积，设计合成II型FLT3不可逆共价抑制剂，为治疗AML提供新型候选药物。

The over-expression of type III receptor tyrosine kinase FLT3 can cause acute myeloid leukemia (AML), and mutation can lead to drug resistance. Covalent inhibitors have become a hot research topic to solve drug resistance of tumors. In the previous study, this project used Linifanib as a template to obtain a type II irreversible covalent inhibitor S35, it had high inhibitory activity against wt-FLT3 (IC50=1.4nM), FLT3-ITD (IC50=1.2nM), FLT3-D835Y (IC50=1.7nM), and its Michael receptor could form covalent bond with Cys807 in wt-FLT3. However, the inhibitory activity against FLT3-ITD-F691L (IC50=16.1nM) was weak, the reason was that the phenyl ring in S35 formed a pi-pi interaction with the gate Phe691 in wt-FLT3. Unfortunately, this pi-pi interaction disappeared after second mutation that the phenylalanine at 691 position changed into leucine, thus resulting the change of molecular conformation and loss of covalence, which led to drug resistance. This project will adopt drug design methods including skeleton transition, bioelectronics to modify the structure of S35, adjust the molecular conformation of Michael receptor and link chain, avoid the accumulation of pi-pi interaction, design and synthesize novel type II FLT3 irreversible covalent inhibitors, and provide a new drug candidate for the treatment of AML.