AUTHOR=Shi Jianghua , Wang Luo , Zeng Xuanwei , Xie Chengzhi , Meng Zhaowei , Campbell Anahit , Wang Lulu , Fan Heli , Sun Huabing 

TITLE=Precision-engineered PROTACs minimize off-tissue effects in cancer therapy

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=Volume 11 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2024.1505255

DOI=10.3389/fmolb.2024.1505255

ISSN=2296-889X

ABSTRACT=Proteolysis-targeting chimeras (PROTACs) offer a groundbreaking approach to selectively degrade disease-related proteins by utilizing the ubiquitin-proteasome system. While this strategy shows great potential in preclinical and clinical settings, off-tissue effects remain a major challenge, leading to toxicity in healthy tissues. This review explores recent advancements aimed at improving PROTAC specificity, including tumor-specific ligand-directed PROTACs, pro-PROTACs activated in tumor environments, and E3 ligase overexpression strategies. Innovations such as PEGylation and nanotechnology also play a role in optimizing PROTAC efficacy. These developments hold promise for safer, more effective cancer therapies, though challenges remain for clinical translation.