PROTAC 2.0: Expanding the frontiers of targeted protein degradation

Abstract

Proteolysis targeting chimera (PROTAC) technology has revolutionized targeted protein degradation via the ubiquitin-proteasome system. Despite their efficacy in degrading previously undruggable proteins, classical PROTACs face challenges such as poor permeability, dose-dependent effects, and off-target toxicity, prompting the rise of next-generation PROTACs (PROTAC 2.0). This review explores emerging PROTAC-based strategies aimed at enhancing selectivity, bioavailability, and pharmacokinetics. We discuss innovative approaches such as photoactivable PROTACs, hypoxia-responsive degraders, dual and trivalent PROTACs, and antibody-conjugated degraders. Additionally, nanotechnology-based delivery systems are highlighted as promising tools to overcome membrane permeability issues. By analyzing these novel strategies, we highlight the evolution of PROTACs and their growing therapeutic potential. Advances in PROTAC 2.0 technologies are expected to expand their clinical applications, offering more selective and efficient degradation mechanisms.

Keywords: PROTAC; degrader; nano-PROTAC; targeted protein degradation (TPD); ubiquitin–proteasome system (UPS).