Citation: Si Ha, Jiacheng Zhu, Hua Xiang, Guoshun Luo. Hydrophobic tag tethering degrader as a promising paradigm of protein degradation: Past, present and future perspectives[J]. Chinese Chemical Letters, ;2024, 35(8): 109192. doi: 10.1016/j.cclet.2023.109192 shu

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

Si Ha ¹ ,
Jiacheng Zhu ¹ ,
Hua Xiang ^*, ,
Guoshun Luo ^*,

State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China

xianghua@cpu.edu.cn

gsluo@cpu.edu.cn

Received Date: 19 August 2023
Revised Date: 6 October 2023
Accepted Date: 10 October 2023
Available Online: 13 October 2023

Figures(20)

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 degradation, thus circumventing the limitations associated with traditional small molecule inhibitors. Hydrophobic 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 degradation 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 relationships, 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 potential of HyTTDs.
- Targeted protein degradation (TPD),
- Hydrophobic tag,
- Degrader,
- Hydrophobic tag tethering degrader (HyTTD),
- Targeted therapy
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