蛋白质精氨酸甲基转移酶5抑制剂的设计、合成及活性评价

Design, synthesis and activity evaluation of protein arginine methyltransferase 5 inhibitor

蛋白质精氨酸甲基转移酶5(PRMT5)是人体中重要的II型甲基转移酶,可以催化多种组蛋白及非组蛋白的对称性双甲基化,并在多种肿瘤中高表达,是一种潜在的治疗癌症的新靶点。本文根据已报道的EPZ015666与PRMT5复合物晶型,并分析其相互作用模式,开展对GSK3326595(原为EPZ015938)的结构改造,使用构象限制原理设计合成了16个化合物,经过生物学评价发现化合物B8和C系列6个化合物均具备与GSK3326595相当的PRMT5抑制活性。Caco-2细胞透膜性实验表明化合物C3、C4的透膜性较差,可能是细胞抗增殖活性较差的一个原因,为下一步结构设计提供思路。

Protein arginine methyltransferase 5(PRMT5)is an important type II human methyltransferase.It catalyzes the symmetrical double-methylation of many histones and non-histones,and it is highly expressed in many kinds of tumors.PRMT5 has been proven to be a potential new target for cancer treatment.Based on the reported crystal complex of EPZ015666 with PRMT5,a series of new compounds was designed using GSK3326595(EPZ015938)as the lead compound and using the conformational restriction approach.We found that compounds B8 and the C series of derivatives displayed enzyme inhibitory activity comparable to that of GSK3326595.Compounds C3 and C4 showed poor permeability in Caco-2 cells,and that might be one of the reasons for their poor anti-proliferative activity against Z-138 cells.These data provide insights for further structural optimization.