基于PROTAC技术靶向降解FAK蛋白的研究进展  

Recent progress in targeting degradation of FAK based on PROTAC

作　　者：徐颖若 张沁松 吴菁艺 鲍润菲 曾申昕 XU Ying-ruo;ZHANG Qin-song;WU Jing-yi;BAO Run-fei;ZENG Shen-xin(College of Pharmacy,Hangzhou Medical College,Hangzhou 310053,China)

机构地区：[1]杭州医学院药学院,浙江杭州310053

出　　处：《药学学报》2021年第6期1571-1579,共9页Acta Pharmaceutica Sinica

基　　金：浙江省教育厅一般科研项目(Y202045350)。

摘　　要：局部黏着斑激酶(focal adhesion kinase,FAK)是一种非受体细胞内酪氨酸激酶,其同时具有激酶依赖和非激酶依赖的支架功能,在肿瘤的发生发展及转移侵袭中均起到重要作用,被认为是抗肿瘤药物研发的重要靶点。然而,传统的小分子抑制剂只能抑制其激酶活性,难以靶向非激酶依赖的支架功能。因此,迫切需要新颖的策略来研究FAK靶点,为FAK靶点的成药性及其相关药物的研发奠定基础。蛋白水解靶向嵌合体(proteolysis targeting chimera,PROTAC)技术是一种新兴的药物研发策略,其能招募E3泛素连接酶,特异性泛素化靶蛋白并通过蛋白酶体系统靶向降解目的蛋白。PROTAC的独特作用机制能靶向降解FAK蛋白,从而消除FAK的支架功能,极大吸引了科研人员的兴趣。本文简述了FAK蛋白、信号通路及小分子抑制剂,系统综述了基于PROTAC技术靶向降解FAK蛋白的最新研究进展,最后总结并展望了基于PROTAC技术靶向FAK蛋白的发展前景。Local focal adhesion kinase(FAK)is a non-receptor intracellular tyrosine kinase that plays an important role in tumor initiation,development,metastasis and invasion,and is considered to be an important target for the development of antineoplastic drugs.It has both kinase-dependent and non-kinase-dependent scaffolding functions.However,traditional small molecular inhibitors can only inhibit its kinase-dependent activity,so it is difficult to target the kinase-independent scaffolding function.Therefore,there is an urgent need for novel strategies to enhance FAK targeting to lay the foundation for determining the druggability and discovery of FAK inhibitors.Proteolysis targeting chimera(PROTAC)is a new drug development strategy that can recruit E3 ligase to specifically ubiquitinylate target proteins for degradation through the proteasome system.The unique mechanism of action of the PROTAC system could be used to target and degrade the FAK protein,thus eliminating the scaffolding function of FAK.In this review,FAK protein,the signaling pathway,and small molecule inhibitors are briefly described,and the latest research progress in targeting the degradation of FAK using PROTAC technology is summarized.

关 键 词：局部黏着斑激酶 靶向蛋白水解的嵌合体 小分子抑制剂 E3泛素连接酶 药物研发 

分 类 号：R916[医药卫生—药学]