蛋白降解靶向嵌合体的研究进展  

Research Progress on Proteolysis Targeting Chimeras

作　　者：马恒元 柯志强[3] 苏正定[1] MA Hengyuan;KE Zhiqiang;SU Zhengding(Cooperative Innovation Center of Industrial Fermentation(Ministry of Education&Hubei Province),Hubei University of Technology,Wuhan 430068;Jiangsu Hengrui Pharmaceuticals Co.,Ltd.,Lianyungang 222000;Hubei Key Lab.of Diabetes and Angiopathy,Xianning Medical College,Hubei University of Science and Technology,Xianning 437100)

机构地区：[1]湖北工业大学工业发酵省部共建协同创新中心,湖北武汉430068 [2]江苏恒瑞医药股份有限公司,江苏连云港222000 [3]湖北科技学院咸宁医学院,糖尿病心脑血管病变湖北省重点实验室,湖北咸宁437100

出　　处：《中国医药工业杂志》2024年第11期1467-1476,1504,共11页Chinese Journal of Pharmaceuticals

摘　　要：传统的小分子激酶抑制剂药物面临着诸多挑战,如易产生耐药性和部分靶点不可成药的问题。蛋白降解靶向嵌合体(PROTAC)技术利用细胞内固有的泛素-蛋白酶体系统,实现对靶蛋白(POI)的降解以治疗疾病,可避免靶点不可成药和耐药性的限制,有望克服小分子抑制剂的局限。目前多款PROTAC已进入临床试验阶段,成为许多疾病潜在的治疗方式。文章综述了PROTAC的生物学机制、技术优势、分子设计及其临床应用前景,以期为其药物开发与临床应用提供参考。Traditional small molecule kinase inhibitor drugs face numerous challenges,such as the propensity for drug resistance and the problem that some targets are undruggable.The proteolysis targeting chimera(PROTAC)technology utilizes the inherent ubiquitin-proteasome system in cells to achieve the degradation of proteins of interest(POI)for treating diseases,which can avoid the limitations of undruggable targets and drug resistance.Therefore,the PROTAC technology is expected to overcome the limitations of small molecule inhibitors.At present,some PROTACs have entered the clinical trial stage and are expected to become potential treatment methods for many diseases.This review introduces the biological mechanism,technical advantages,molecular design and clinical application prospects of PROTAC,hoping to provide a reference for its drug development and clinical application.

关 键 词：不可成药靶点 泛素-蛋白酶体系统 蛋白降解靶向嵌合体 临床试验 研究进展 

分 类 号：R915[医药卫生—微生物与生化药学] R979.1*9[医药卫生—药学]