研究表明menin-MLL相互作用是混合谱系白血病个性化治疗的重要靶标，为混合谱系白血病提供了崭新的治疗思路。目前靶向menin-MLL相互作用小分子抑制剂的报道较少，至今尚未有进入临床的药物，有着巨大的研究空间和前景。本项目以menin-MLL相互作用为靶标，基于“老药二次开发”的策略，通过对现有临床药物进行筛选，结合生物活性评价确证及结构优化。前期工作中我们筛选出抗腹泻药物“洛哌丁胺”对menin-MLL相互作用有一定抑制（IC50=69.58 µM），对其老药骨架初步改造后获得了分子水平和细胞水平都有活性的苗头化合物（DC_YM21, IC50=0.83 µM，MV4;11: IC50=1.67 μM），通过本项目的实施，我们将基于苗头化合物进行深入的结构优化及构效关系研究，以期获得成药性高的Menin-MLL靶向小分子抑制剂，为MLL白血病治疗提供高效、低毒的药物先导结构。

Targeting the protein-protein interactions between menin and MLL represents an attractive strategy for curing MLL leukemia. Till now, the reports about small molecule inhibitors of the menin-MLL interaction are rare and no clinical drug available. Therefore, there are great research space and prospect to develop some molecules with good druggability. In our project, we utilized a shape-based scaffold hopping approach to analyse the recent small-molecule inhibitors for menin-MLL and we screened a collection of clinical compounds to identify the inhibitors targeting this interface. We have discovered that the antidiarrheals loperamide displays, previously unreported, mild inhibition for the menin-MLL interaction (IC50 = 69.58 µM). Further chemical modification combined with structure-activity relationship studies are applied to repurpose the loperamide scaffold, resulting in several improved loperamide-derived analogues. DC_YM21, one of the potent novel scaffold molecules showed good activities in our FP assays (IC50 = 0.83 µM) and cell viability assays (IC50 = 1.67 μM). In order to find more potent inhibitor targeting on the menin-MLL interaction,we will conduct deep optimization for the drugability and structure-activity relationship studies. In conclusion, this project will shed new light on the development of lead compound with high activity and low toxicity for MLL-mediated leukaemogenesis.