新一代促进微管降解并能克服多药耐药的微管降解剂SKLB-2H作用位点和抗耐药分子作用机制研究

微管作为抗肿瘤药物的靶点具有稳定、高效等特点，是抗肿瘤药物研究最炙手可热的靶点，抗微管药物和微管蛋白复合物的结构生物学研究对揭示药物影响微管动态平衡的分子机理和指导克服耐药的抗微管新药设计具有重要意义。本项目前期通过X射线晶体衍射技术、生物化学方法，发现了一类具有抑制微管聚合、能够时间、浓度依赖的促进微管蛋白异二聚体的降解。而不影响其mRNA水平、且能克服耐药的的新型微管抑制剂降解剂，我们将这类化合物首次命名为新型微管降解剂，其中活性最好的化合物该命名为SKLB-2H。本项目将对微管降解剂SKLB-2H开展如下工作：（1）通过竞争结合实验确定SKLB-2H的结合位点；（2）解析SKLB-2H促进微管蛋白降解的具体作用机制；（3）解析SKLB-2H与微管蛋白复合物的晶体结构，从结构生物学角度阐述为何SKLB-2H促进微管蛋白降解。

As the most hot target of antitumor drugs, microtubule is a stable and efficient target. Structural biology of anti-microtubule drugs and tubulin complexes could reveal how the drug affect microtubule dynamic balance, and this molecular mechanism is important for drug design to overcome drug-resistant. In our previous study, using X-ray crystallography and biochemical methods, we have found a serious small molecule could promote the degradation of tubulin heterodimers in time and concentration dependent manner without affecting its mRNA level. Also, these compounds could overcome mult-drug resistance. we first named these compounds as a new microtubulin degradation agents, Among which the most active compound is SKLB-2H. This project will carry out the following work on the microtubule degradation agent SKLB-2H: (1) determining the binding site of SKLB-2H by competitive binding experiments; (2) analyzing the specific mechanism of action of SKLB-2H for promoting tubulin degradation; (3 ) Analyzes the crystal structure of the SKLB-2H and tubulin complexes, elucidating from a structural biology perspective why SKLB-2H promotes tubulin degradation.