蛋白激酶C与免疫系统的关系及其抑制剂的研究进展

Progress in the relationship between protein kinase C and immune system and its inhibitors

目的阐述蛋白激酶C(protein kinase C,PKC)与免疫系统的关系并综述近年来以PKC为靶点按不同结构修饰的免疫抑制剂研究。方法根据已报道的蛋白激酶C参与的免疫系统有关的细胞信号转导通路和PKC免疫抑制剂结构修饰的文献,对PKC与免疫系统的关系进行简单概述,并将具有免疫抑制活性的PKC抑制剂以结构分类综述。结果蛋白激酶C在免疫系统中发挥着重要作用,其与很多免疫疾病的发生密切相关。设计合成小分子化合物来抑制蛋白激酶C活性成为治疗自身免疫疾病及其他免疫性疾病的最佳策略。通过高通量筛选、结构修饰等方法已获得了大量以蛋白激酶C不同亚型尤其是PKCθ为靶点的高效低毒新型免疫抑制剂,如AEB071、PKC412、LY3176正处在临床前和临床研究阶段。结论随着研究的不断深入,会有更多的具有免疫抑制活性的蛋白激酶C抑制剂进入临床研究或上市。

Objective To reviewthe research progress of the immunosuppressors targeting protein kinase C,PKC）,as well as the relationship between PKC and immune system. Methods According to references about PKC isozymes in signal transduction of immune system and the PKC inhibitors with immunosuppressive activity,the immunosuppressors targeting PKC were divided into five categories by their structures. The relationship between PKC and immune system was summarized. Results Many immunosuppressors with high activity,good selectivity and fewside effects targeting different PKC isozymes,especially PKCθ,had been obtained by some technologies,such as high throughput screening（ HTS） and structural modification,and many of them were in preclinical and clinical phases,among them,AEB071,PKC412 and LY3176 had been in the II,III and III phases of clinical research. Conclusions With the further research,there will be more PKC inhibitors with immunosuppressive activity which can enter into clinical studies or come into the market.