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组蛋白甲基化是表观遗传学的标志之一,其调节紊乱与许多疾病有联系.恶性脑瘤域(MBT)家族蛋白是一类能够识别组蛋白赖氨酸甲基化信号的蛋白,L3MBTL3是该家族中代表性的蛋白之一,它与染色质转录抑制、造血功能、肿瘤形成等都有关系.开发L3MBTL3小分子抑制剂可以辅助阐明其生物学作用和验证其靶点成药性.首先通过筛选嘧啶并二氮化合物库,得到了L3MBTL3的活性化合物1,接着按照已报道L3MBTL3抑制剂的结构特点进行构效关系研究,最终得到了四个IC_(50)值小于1μmol·L~(-1)新颖的L3MBTL3抑制剂.
Histone methylation is one of the epigenetic markers, and its regulation disorder is associated with many diseases.The malignant brain tumor (MBT) family of proteins is a class of proteins that recognize histone lysine methylation signals, L3MBTL3 is one of the most representative proteins in this family, which is related to chromatin transcription inhibition, hematopoiesis, tumor formation, etc. The development of L3MBTL3 small molecule inhibitors can help elucidate its biological function and verify its target drug-induced. First of all, by screening the pyrimidinodiazepine compound library, the active compound 1 of L3MBTL3 was obtained, and then the structure-activity relationship of the reported L3MBTL3 inhibitor was studied. Finally, four IC50 values of less than 1 μmol·L- (-1) novel L3MBTL3 inhibitor.