新型选择性LSD1抑制剂的发现及抗MLL融合型白血病作用机制的研究

At present, epigenetics related enzymes have becomed a hot topic in anti-tumor therapy. According to the related research progress rapidly, the Lysine specific demethylase 1(LSD1) is considered as particularly sensitive drug target in MLL-Mixed Lineage Leukemia, which is no symptomatic drugs on clinical nowadays. There are 4 drug candidates in clinical stage, but our country is still blank. In the preliminary work, a lot of novel compound structure skeletons were found by high-throughput screening of more than 300,000 compounds, which have been established using a LSD1 demethylation assay，and we designed a series of new compounds combining the structure with the preferred conformation of the tranylcypromine. We found a number of active compounds similar to the clinical drug candidates by biochemical and cellular assays. Based on the good work, we will optimize the structure-activity relationship further. Toward the aim of developing LSD1 potential candidate compounds with independent intellectual property rights, we will use approaches according to combiation biochemical LSD1 assay platform, the growth and differentiation of MLL-Mixed Lineage leukemia cells, pharmacodynamics in vivo, pharmacokinetics to identify the function and mechnism of candidate compounds quickly. Through this study, it will lay a solid foundation for the discovery of anti-MLL-Mixed Lineage leukemia LSD1 candidate drugs.

靶向表观遗传调控酶是近年抗肿瘤药物研究热点。其中靶向抑制赖氨酸特异性去甲基化酶LSD1对临床无对症药物的MLL融合型白血病尤其敏感，相关研究进展迅速，已有4个临床阶段候选药物，但我国尚是空白。前期已建立靶向LSD1的分子水平高通量筛选体系，完成大于30万化合物的高通量筛选，获得新颖化合物结构骨架，并结合反苯环丙胺的优势构象进行活性化合物的结构优化和分子细胞水平的活性与机制评价，发现多个与临床药物活性相当的先导化合物。本研究拟在良好工作基础上，进一步开展构效关系优化，以分子水平LSD1组合筛选平台为基础，以细胞水平MLL融合型白血病细胞增殖和分化为评价模型，结合整体动物水平的药物代谢和慢性药效结果，发现具有自主知识产权的优于临床LSD1抑制剂的更具成药潜力的候选活性化合物，为抗MLL融合型白血病的LSD1候选药物的发现奠定坚实基础。

赖氨酸特异性去甲基化酶(LSD1)在多种肿瘤的发生发展中起着重要作用，已成为抗肿瘤的药物靶标，其中MLL融合型白血病患者就是其敏感人群，目前国际上相关药物研发工作开展的如火如荼。前期工作采用高通量筛选获得新颖化合物结构骨架结合反苯环丙胺的优势构象进行抑制剂的改造和合成，结合体内外药效学和作用机制研究，已发现多个体内外具有生物功能的活性先导化合物。本研究拟以此为切入点，依托体外酶分子水平LSD1组合筛选平台为基础，以MLL融合型白血病细胞增殖和分化为指针，整体动物的抑瘤效果为导向，结合候选化合物初步成药性分析，开展LSD1抑制剂的优化和候选化合物的发现工作。通过本课题的开展，共合成145个全新结构的LSD1小分子抑制剂，并建立了完备的体内外药效学研发平台。依托化合物结构改造及药效学研发平台其中发现了候选化合物DC551040，其在分子、细胞和整体动物水平上的活性均优于临床候选药物GSK2879552，并具有良好的口服药代性质及优良的安全治疗窗口，同时多个备选化合物整体上体现出优于GSK2879552的特质。候选化合物DC551040是高效、高选择性的、低毒的特异性LSD1抑制剂，为抗MLL融合型白血病的LSD1候选药物的发现提供了新的研发思路和候选化合物。