Hydrophobic tag-based protein degradation: Development, opportunity and challenge

Targeted protein degradation (TPD) has emerged as a promising approach for drug development, particularly for undruggable targets. TPD technology has also been instrumental in overcoming drug resistance. While some TPD molecules utilizing proteolysis-targeting chimera (PROTACs) or molecular glue strategies have been approved or evaluated in clinical trials, hydrophobic tag-based protein degradation (HyT-PD) has also gained significant attention as a tool for medicinal chemists. The increasing number of reported HyT-PD molecules possessing high efficiency in degrading protein and good pharmacokinetic (PK) properties, has further fueled interest in this approach. This review aims to present the design rationale, hydrophobic tags in use, and diverse mechanisms of action of HyT-PD. Additionally, the advantages and disadvantages of HyT-PD in protein degradation are discussed. This review may help inspire the development of more HyT-PDs with superior drug-like properties for clinical evaluation.

Automated summary

Targeted protein degradation (TPD) is a promising approach for drug development, especially for undruggable targets. While some TPD molecules utilizing PROTACs or molecular glue strategies have been approved or evaluated, hydrophobic tag-based protein degradation (HyT-PD) has gained attention for medicinal chemists. This review provides an overview of the design rationale, hydrophobic tags, and diverse mechanisms of action of HyT-PD, as well as the advantages and disadvantages in protein degradation.