磷酸化Bcl-2蛋白的BH3模拟分子-基于细胞模型的定向筛选和构效关系研究

磷酸化修饰的Bcl-2蛋白(pBcl-2)会赋予肿瘤细胞新的抗凋亡分子机制。但是，利用多种间接方法研究pBcl-2的功能，得出的结论截然相反。本课题致力于获得第一个（系列）直接结合pBcl-2的功能区：BH3结构域的小分子，作为直接研究其功能的工具，希望揭示Bcl-2磷酸化的真正意义。基于磷酸化导致了BH3构像改变的假设，本课题拟在Bcl-2蛋白的BH3模拟分子: S1的基础上，将它的系列衍生物作用于Bcl-2持续磷酸化的肿瘤细胞模型，定向筛选以发生改变的BH3沟槽为特异性作用靶点的有机小分子。通过对这些小分子的构效关系研究，我们将首次获得pBcl-2蛋白的BH3沟槽的结构信息，揭示Bcl-2通过磷酸化获得新功能的结构基础。利用这些小分子,我们将研究pBcl-2的蛋白质相互作用与细胞凋亡的时空关系，明确pBcl-2的功能。不仅可能解决学术争议，还可能为原创的分子靶向抗癌药提供更理想的选择。

Bcl-2 phosphorylation confers cancer cells novel antiapopotic molecular mechanism. However, controversial conclusions were established on the function of phosphorylated Bcl-2 (pBcl-2)by using indirect methods. In order to reveal the biological function and significance of pBcl-2, the subject is committed to acquire the first small molecule tools that directly bind into the active site of pBcl-2, BH3 groove, to directly study the function of pBcl-2. Based on the hypothesis that phosphorylation results in the conformational change of BH3 grooves,we planned to use Bcl-2 constitutively phosphorylated cancer cell-directed screening method to find candidate molecules from BH3 mimetic, S1’ derivatives. Through the structural-activity relationship study of these pBH3 mimetics, we would acquire structural information of BH3 grooves of pBcl-2 for the first time, and the strucrural basis of new mechanism conferred by pBcl-2. We would reveal biological function and significance of pBcl-2 through analysing time and spatial relationships between pBcl-2 inhibition and apoptosis.Moreover, the antiapoptotic molecular pathway and mechanism controlled by Bcl-2 family could be elucidated. The subject could not only solve the controversial issues, but also provide an potential drug lead for targeted cancer therapy.