Hydrophobic tag tethering degrader as a promising paradigm of protein degradation:Past,present and future perspectives  

作　　者：Si Ha Jiacheng Zhu Hua Xiang Guoshun Luo 

机构地区：[1]State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry,China Pharmaceutical University,Nanjing 211198,China

出　　处：《Chinese Chemical Letters》2024年第8期187-200,共14页中国化学快报（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China(Nos.82103978,81874286);the Natural Science Foundation of Jiangsu Province(No.BK20210423);“Double-First-Class”University Project(Nos.CPU 2018PZQ02,CPU 2018GY07).

摘　　要：Small molecule inhibitors have dominated the pharmaceutical landscape for a long time as the primary therapeutic paradigm targeting pathogenic proteins.However,their efficacy heavily relies on the amino acid composition and spatial constitution of proteins,rendering them susceptible to drug resistance and failing to target undruggable proteins.In recent years,the advent of targeted protein degradation(TPD)technology has captured substantial attention from both industry and academia.Employing an event-driven mode,TPD offers a novel approach to eliminate pathogenic proteins by promoting their degrada-tion,thus circumventing the limitations associated with traditional small molecule inhibitors.Hydropho-bic tag tethering degrader(HyTTD)technology represents one such TPD approach that is currently in the burgeoning stage.HyTTDs employ endogenous protein degradation systems to induce the degrada-tion of target proteins through the proteasome pathway,which displays significant potential for medical value.In this review,we provide a comprehensive overview of the development history and the reported mechanism of action of HyTTDs.Additionally,we delve into the physiological roles,structure-activity re-lationships,and medical implications of HyTTDs targeting various disease-associated proteins.Moreover,we propose insights into the challenges that necessitate resolution for the successful development of HyTTDs,with the ultimate goal of initiating a new age of clinical treatment leveraging the immense po-tential of HyTTDs.

关 键 词：Targeted protein degradation(TPD) Hydrophobic tag Degrader Hydrophobic tag tethering degrader(HyTTD) Targeted therapy 

分 类 号：R914[医药卫生—药物化学]