Hedgehog信号通路耐药型Smoothened受体蛋白抑制剂的发现

Hedgehog(Hh)信号通路的异常激活会引发恶性肿瘤。Smoothened(Smo)蛋白是Hh信号通路中主要的传导器，Smo抑制剂可以阻断Hh信号通路的异常激活。但是Smo蛋白的突变会使这些抑制剂产生耐药性。突变的Smo D473H蛋白与这些抑制剂的亲和力大幅下降，并重新激活Hh信号通路，使肿瘤复发。以Smo D473H蛋白为靶标的药物设计策略为耐药性的解决方案提供新的思路。本课题借助多学科交叉的优势，构建耐药型Smo D473H受体蛋白模型，与结构多样性的小分子化合物库进行分子对接，解析得到的靶点结构模式进行合理药物设计、定向合成；然后将筛选得到活性化合物用于进一步构效关系研究。经几轮筛选后，期望能发现活性良好的抗肿瘤先导化合物，用于体外抗细胞增殖研究和动物体内药效学和药动学研究，寻找具有开发应用价值的抗肿瘤候选化合物。

Aberrant Hedgehog (Hh) pathway signaling has been implicated in malignant tumor. Smoothend (Smo) receptor is a key signal transducer and Smo inhibitors could block the Hh pathway. As a matter of fact, drug resistance and tumor relapse occur in the mutations in Smo, since the affinity of mutational Smo D473H with the inhibitors launched is weaken sharply. It is a feasible avenue to develop drug design strategy targeting Smo D473H. In this subject, Smo D473H model is constructed and is virtually docked with small molecules. The analysis for the crystal structure of Smo D473H bound to small molecules is conducive to rational drug design and oriented synthesis. Base on above, compounds with diverse structures library is built to screen novel potent compounds before the analysis on structure-activity relationship. It is expected to discovery highly efficacious lead compounds after several rounds of screening. Moreover, their antiproliferative effect in vitro, potency and pharmacokinetic parameters in vivo are investigated to look for antitumor candidates worth further clinical trial.