靶向PRC2相关蛋白小分子抑制剂的研究进展

The development of small-molecule inhibitors that target PRC2-related proteins

多梳抑制复合物(polycomb repressive complex 2,PRC2)的异常表达与多种疾病的形成、发展相关,抑制正常或过度活跃的PRC2可以在几种癌症中降低细胞存活率并抑制肿瘤生长,因此,相关小分子抑制剂的研发成为了当前表观遗传学相关抗肿瘤策略的热点领域。靶向enhancer of zeste homologue 2(EZH2)的S-腺苷-L-甲硫氨酸(S-adenosyl-L-methionine,SAM)结合位点的小分子抑制剂中已有药物经过FDA批准上市,然而,此类抑制剂的获得性耐药性问题同时值得关注。靶向胚胎外胚层发育蛋白(embryonic ectoderm development,EED)的两个不同结合位点的药物也在不断向前发展,EZH2-EED PPI抑制剂的研发因全新且独特的作用机制受到广泛关注。本文综述了各类靶向PRC2相关蛋白小分子抑制剂的研究进展,为相关药物的进一步研发提供参考。

Abnormal expression of polycomb repressive complex 2(PRC2)is related to the development of a variety of diseases.Inhibition of normal or overactive PRC2 can reduce cell survival and inhibit tumor growth in several cancers.Therefore,the identification and development of small molecule inhibitors has become an active field of current epigenetic-related anti-tumor strategies.A small molecule inhibitor targeting the S-adenosyl-Lmethionine(SAM)binding site of enhancer of zeste homologue 2(EZH2)has been approved by FDA.However,acquired drug resistance is of concern.Drugs targeting two different binding sites of embryonic ectoderm development(EED)are also being developed.The development of EZH2-EED proton pump inhibitor has attracted extensive attention due to its unique mechanism of action.In this paper,we review the research progress on various small molecule inhibitors that target PRC2-related proteins to provide a basis for further research and development of related drugs.