Advancing Design Strategy of PROTACs for Cancer Therapy
Hang Luo1, Yuan Tian2, Razack Abdullah2
1School of Chinese Medicine Faculty of Medicine The Chinese University of Hong Kong Hong Kong SAR China.
Abstract:
Proteolysis targeting chimeras (PROTACs) have emerged as a groundbreaking class of anticancer therapeutics. These bifunctional molecules harness the endogenous ubiquitin-proteasome system to facilitate the degradation of targeted proteins of interest (POIs). Notably, the clinical translation of PROTACs has gained substantial momentum, with many PROTAC candidates targeting various cancers currently undergoing clinical trials (Phase I-III). However, the rational design of high-efficacy PROTAC compounds remains a significant challenge. In this review, we presented a comprehensive overview of POI ligands, E3 ligands, and their interconnected linkers in PROTAC design, including their generation, structural optimization, and contribution to degradation efficiency and selectivity. Particularly, we analyzed the distinct preferences of various types of POI ligands (small molecule, nucleic acid, and peptide) toward specific targets. Furthermore, we emphasized the significant role of artificial intelligence technology in PROTAC design, including POI/E3 ligands discovery and linkers generation or optimization. We also summarized the applications and challenges of PROTACs in cancer therapy. Finally, we discussed the future development of PROTAC by combining multidisciplinary technologies and novel modalities for cancer therapy. Overall, this review aims to provide valuable insights for advancing PROTAC design strategies for cancer therapy.
Insights
Proteolysis targeting chimeras (PROTACs) offer a novel approach to cancer therapy by degrading target proteins. This review details PROTAC design, focusing on ligands, linkers, and AI, to improve anticancer efficacy.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Proteolysis targeting chimeras (PROTACs) represent a significant advancement in anticancer therapeutics.
- PROTACs utilize the body's natural protein degradation system to eliminate disease-causing proteins.
Purpose of the Study:
- To provide a comprehensive review of PROTAC design strategies for enhanced anticancer efficacy.
- To analyze the roles of protein of interest (POI) ligands, E3 ligands, and linkers in PROTAC development.
- To highlight the impact of artificial intelligence (AI) on PROTAC discovery and optimization.
Main Methods:
- Review of existing literature on PROTAC design principles and clinical applications.
- Analysis of different types of POI ligands (small molecule, nucleic acid, peptide) and their target specificities.
- Examination of AI applications in identifying PROTAC components and optimizing linker strategies.
Main Results:
- PROTAC design involves careful selection and optimization of POI ligands, E3 ligands, and linkers to achieve high degradation efficiency and selectivity.
- Various ligand types exhibit distinct preferences for specific targets, influencing PROTAC effectiveness.
- AI significantly aids in discovering novel ligands and optimizing linker sequences for improved PROTAC performance.
Conclusions:
- Advancements in PROTAC design, particularly through AI and multidisciplinary approaches, hold great promise for improving cancer therapy.
- Understanding the interplay between PROTAC components is crucial for developing next-generation anticancer agents.
- Future PROTAC development will likely integrate novel technologies for more effective cancer treatment strategies.
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