多发性骨髓瘤全新靶点AHA1的发现及其小分子抑制剂的研发

多发性骨髓瘤（multiple myeloma，MM）是一种克隆性浆细胞恶性肿瘤，传统药物治疗效果有限且容易复发，寻找新靶点克服耐药、抑制复发意义重大。目前，针对MM的新靶点药物已成为药学界的热点。本课题组前期首次发现Hsp90α的辅酶蛋白AHA1在MM患者中高表达，并促进MM细胞的恶化，通过抑制AHA1可有效抑制MM细胞增殖，有望成为治疗MM新靶点。我们基于前期筛选得到的苗头化合物SL1，通过计算模拟、定点突变、生物活性测试等方法预测并验证了关键性氨基酸K137和N131，确定了AHA1小分子结合位点。本项目将通过基于结构的药物设计，对苗头化合物SL1进行结构改造，以期得到理化性质和活性更优的小分子化合物。此外，由于AHA1小分子抑制剂避免直接抑制Hsp90，从而可能避免Hsp90抑制剂的副作用。因此，本项目通过AHA1抑制剂的研发，有望为MM药物的临床治疗提供作用机制全新的候选化合物。

Multiple myeloma (MM) is a kind of clonal plasma cell malignancy. Because of traditional MM drugs with limited efficacy and are easy to relapse, it is of great significance to find new targets to overcome these weakness. Nowadays, new targeted drugs for MM have become a hot spot in the field of pharmaceutical research. Our team found that Hsp90α coenzyme protein AHA1 is highly expressed in MM patients for the first time, and can promote the deterioration of MM cells. Inhibiting AHA1 can effectively inhibit the proliferation of MM cells, which indicates that AHA1 may become a new target for the treatment of MM. Moreover, we discovered the hit compound SL1, and determined its binding site of AHA1 which contains two key amino acids K137 and N131 through computational simulation, site-directed mutagenesis and biological activity test. We aim to obtain several small-molecule compounds with better physical and chemical properties as well as better activity. In addition, AHA1 small-molecule inhibitors can avoid directly inhibiting Hsp90,which may avoid the serious side effects of Hsp90 inhibitors. Therefore, through the research and development of AHA1 inhibitors, this project is expected to provide a new candidate compound for the clinical treatment of MM drugs.