选择性靶向MOZ的小分子：设计合成及其抗MOZ融合相关急性髓系白血病活性研究

组蛋白乙酰转移酶家族中的单核细胞白血病锌指蛋白（MOZ）同MOZ融合相关急性髓系白血病（AML）发生发展密切相关。前期我们基于TCGA数据库和65例患者样本的分析表明，相较于健康人及其他类型白血病患者，该疾病患者MOZ显著高表达，且与预后负相关，MOZ有望成为该疾病治疗的全新靶标。目前已报道的MOZ抑制剂选择性较差。本课题拟在前期高通量筛选获得的选择性良好、活性较高苗头化合物DYT-1基础上，结合MOZ活性口袋关键特异性残基，综合运用基于结构设计、靶向蛋白降解(PROTAC)策略等手段设计合成结构新颖、特异性靶向MOZ的小分子抑制剂、降解剂。部分已合成的苯并咪唑-嘧啶类小分子抑制剂展现了良好的选择性，且对三例患者原代细胞展现了强效抗增殖能力。通过系统的生物活性和构效关系研究，最终获得选择性高、活性好、药代动力学性质良好的靶向MOZ小分子，为MOZ融合相关AML精准治疗提供新策略。

Monocytic leukemia zinc finger protein (MOZ), belonging to MYST family of Histone acetyltransferases, is closely related to the occurrence and development of acute myeloid leukemia (AML) with MOZ fusion. The analysis of TCGA database and 65 AML with MOZ fusion samples displayed that the expression of MOZ was higher than healthy person and other types of leukemia with inverse correlation to prognosis, which suggested that MOZ may be a new and promising target for AML with MOZ fusion therapy. However, it is a pity that all the reported MOZ inhibitors were with low selectivity. Based on DYT-1 with promising potency and selectivity that was discovered by the means of high throughput screening, a series of inhibitors and degradation agents had been designed and synthesized through different drug design approaches including structure-based design and PROTAC technology. Some of the synthesized compounds with benzimidazol-pyrimidine scaffold had showed good selectivity and strong anti-proliferation potency on primary AML cells. We will further evaluate the activity and conclude the SAR to discovery these compounds targeting MOZ with high selectivity, strong activity and good pharmacokinetic property. The significance of our work lies in providing a new strategy for precise therapy of AML with MOZ fusion.