蛋白质的拟素化通路在肺癌中的激活和化学靶向干预  

Highly activated neddylation pathway in lung cancer and chemical targeted intervention

作　　者：秦向硕 俞卿 李旭凡 熊秀芳 刘鹏渊 韩欣 孙毅 Xiangshuo Qin;Qing Yu;Xufan Li;Xiufang Xiong;Pengyuan Liu;Xin Han;Yi Sun(Cancer Institute of the Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310009,China;Institute of Translational Medicine,Zhejiang University School of Medicine,Hangzhou 310029,China;Thyroid Surgery of Zhejiang Cancer Hospital,Key Laboratory of Zhejiang Translational Medicine for Head and Neck Tumors,Hangzhou 310022,China;Respiratory Department of Run Run Shaw Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310018,China)

机构地区：[1]浙江大学医学院附属第二医院肿瘤研究所,杭州310009 [2]浙江大学医学院转化医学研究院,杭州310029 [3]浙江省肿瘤医院甲状腺外科,浙江省头颈肿瘤转化医学研究重点实验室,杭州310022 [4]浙江大学医学院附属邵逸夫医院呼吸科,杭州310018

出　　处：《中国科学:化学》2025年第4期914-936,共23页SCIENTIA SINICA Chimica

基　　金：国家重点基础研究发展规划(编号:2009CB724100);国家自然科学基金(编号:11221062,11452002)资助项目。

摘　　要：蛋白质拟素化(neddylation)是一种重要的翻译后修饰,通过将NEDD8拟素蛋白共价结合到底物的赖氨酸残基上,从而调节底物的生化活性.此过程是由拟素化激酶(E1)、拟素化耦联酶(E2)和拟素化连接酶(E3)催化的.Cullin家族蛋白是Cullin-RING E3泛素连接酶(CRLs)的核心组分,是拟素化修饰最重要的生理性底物.Cullin被拟素化修饰后,激活CRLs,促进各种关键信号蛋白的泛素化修饰和蛋白酶体降解,从而调节许多关键的生物学功能.近年来的研究表明,拟素化通路在肺癌中高度活化,促进癌细胞的增殖、生存和肺癌的发生发展,并与患者的不良预后呈正相关.因此,靶向拟素化通路已成为开发新型抗肺癌药物研发有前景的策略.本综述首先介绍蛋白质拟素化修饰的生化特性,作为肺癌促进因子的生物信息学分析和细胞学功能验证,然后系统总结了研发拟素化通路小分子抑制剂的方法,至今报道的三大类靶向拟素化通路的小分子抑制剂,以及今后的研究方向.对该研究领域进行了最新的、全面的介绍,以吸引更多的科研工作者投入抗肺癌拟素化小分子抑制剂的研发.Protein neddylation is one type of post-translational modifications in which NEDD8 is attached covalently to a lysine residue of a substrate.Neddylation is catalyzed by E1 activation enzyme(NAE),E2 conjugating enzymes,and E3 ligases.Cullin family members are the physiological substrates of neddylation,and cullin neddylation activates cullin-RING ligases(CRLs),which then promote ubiquitylation and proteasome degradation of many key signal proteins,thus regulating many important biological process.Accumulated data showed that neddylation pathway is highly activated in human lung cancer with positive correlation to poor survival of lung cancer patients.Activated neddylation pathway promotes the proliferation and survival of lung cancer cells,and accelerates lung tumorigenesis.Thus,targeting neddylation has become an attractive approach for the discovery and development of anti-lung cancer therapy.In this review,we first introduce neddylation process,its biochemical properties,and its alterations via bioinformatics analysis,and its known tumor promoting functions in lung cancer.We then list few advanced methodologies/techniques for the discovery of small molecule inhibitors of neddylation enzymes,followed by a comprehensive summary of all known inhibitors of neddylation enzymes.We end the review with brief summary and proposed future perspectives.The goal is to provide a most updated and comprehensive information to the readers of interest,and to draw more scientists to join the effort in the discovery of neddylation inhibitors for anti-cancer therapy.

关 键 词：拟素化修饰 CRL E3连接酶 肺癌 免疫微环境 靶向治疗 小分子抑制剂 

分 类 号：R734.2[医药卫生—肿瘤]