靶向难成药蛋白——蛋白质降解剂的力量  

Targeting the undruggables—the power of protein degraders

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作  者:张超 刘永波 李广晨 杨周立 韩驰 孙秀云 盛春泉 丁克 饶燏 Chao Zhang;Yongbo Liu;Guangchen Li;Zhouli Yang;Chi Han;Xiuyun Sun;Chunquan Sheng;Ke Ding;Yu Rao(State Key Laboratory of Molecular Oncology,MOE Key Laboratory of Protein Sciences,MOE Key Laboratory of Bioorganic Phosphorus Chemistry&Chemical Biology,School of Pharmaceutical Sciences,Tsinghua University,Beijing 100084,China;Changping Laboratory,Beijing 102206,China;School of Pharmacy,Second Military Medical University,Shanghai 200433,China;State Key Laboratory of Chemical Biology,Shanghai Institute of Organic Chemistry,Chinese Academy of Sciences,Shanghai 200032,China)

机构地区:[1]State Key Laboratory of Molecular Oncology,MOE Key Laboratory of Protein Sciences,MOE Key Laboratory of Bioorganic Phosphorus Chemistry&Chemical Biology,School of Pharmaceutical Sciences,Tsinghua University,Beijing 100084,China [2]Changping Laboratory,Beijing 102206,China [3]School of Pharmacy,Second Military Medical University,Shanghai 200433,China [4]State Key Laboratory of Chemical Biology,Shanghai Institute of Organic Chemistry,Chinese Academy of Sciences,Shanghai 200032,China

出  处:《Science Bulletin》2024年第11期1776-1797,共22页科学通报(英文版)

基  金:supported by the National Key R&D Program of China(2021YFA1300200,2021YFA1302100 and 2020YFE0202200);the National Natural Science Foundation of China(82125034,82330115)。

摘  要:Undruggable targets typically refer to a class of therapeutic targets that are difficult to target through conventional methods or have not yet been targeted,but are of great clinical significance.According to statistics,over 80%of disease-related pathogenic proteins cannot be targeted by current conventional treatment methods.In recent years,with the advancement of basic research and new technologies,the development of various new technologies and mechanisms has brought new perspectives to overcome challenging drug targets.Among them,targeted protein degradation technology is a breakthrough drug development strategy for challenging drug targets.This technology can specifically identify target proteins and directly degrade pathogenic target proteins by utilizing the inherent protein degradation pathways within cells.This new form of drug development includes various types such as proteolysis targeting chimera(PROTAC),molecular glue,lysosome-targeting Chimaera(LYTAC),autophagosometethering compound(ATTEC),autophagy-targeting chimera(AUTAC),autophagy-targeting chimera(AUTOTAC),degrader-antibody conjugate(DAC).This article systematically summarizes the application of targeted protein degradation technology in the development of degraders for challenging drug targets.Finally,the article looks forward to the future development direction and application prospects of targeted protein degradation technology.

关 键 词:Undruggables Targeted protein degradation PROTAC Molecule glue DAC LYTAC 

分 类 号:TQ460.1[化学工程—制药化工] TQ936

 

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