Recent breakthroughs in innovative elements, multidimensional enhancements, derived technologies, and novel applications of PROTACs

• Published in: Biomedicine & pharmacotherapy Vol. 180; p. 117584
• Main Authors: Zhang, Si-Han, Zeng, Na, Xu, Jin-Zhou, Liu, Chen-Qian, Xu, Meng-Yao, Sun, Jian-Xuan, An, Ye, Zhong, Xing-Yu, Miao, Lin-Tao, Wang, Shao-Gang, Xia, Qi-Dong
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.11.2024; Elsevier
• Subjects: Drug delivery; Element innovation; Novel application; PROTACs; Spatiotemporal control; Targeting chimeras; PROTACs; Drug delivery; Targeting chimeras; Element innovation; Spatiotemporal control; Novel application
• ISSN: 0753-3322; 1950-6007; 1950-6007
• DOI: 10.1016/j.biopha.2024.117584

Proteolysis Targeting Chimera (PROTAC) is an emerging and evolving technology based on targeted protein degradation (TPD). Small molecule PROTACs have shown great efficacy in degrading disease-specific proteins in preclinical and clinical studies, but also showed various limitations. In recent years, new technologies and advances in TPD have provided additional optimized strategies based on conventional PROTACs that can overcome the shortcomings of conventional PROTACs in terms of undruggable targets, bioavailability, tissue-specificity, spatiotemporal control, and degradation scope. In addition, some designs of special targeting chimeras and applications based on multidisciplinary science have shed light on novel therapeutic modalities and drug design. However, each improvement has its own advantages, disadvantages and application conditions. In this review, we summarize the exploration of PROTAC elements, depict a landscape of improvements and derived concepts of PROTACs, and expect to provide perspectives for technological innovations, combinations and applications in future targeting chimera design. [Display omitted] •Rapid advancements in PROTAC development include innovative warhead, linker, and E3 ligase ligand designs.•Strategies like nanomedicine, spatiotemporal control, and computer-aided design enhance PROTAC potency.•Integrating multidisciplinary technologies rationally could lead to more potent and safer PROTACs.