TY - JOUR
T1 - Advancing Design Strategy of PROTACs for Cancer Therapy
AU - Luo, Hang
AU - Tian, Yuan
AU - Abdullah, Razack
AU - Zhang, Baoting
AU - Ma, Yuan
AU - Zhang, Ge
N1 - This work was supported by the Theme-based Research Scheme (No. T12-201-20R), the Guangdong Basic and Applied Basic Research Foundation (No. 2020A1515110630), the CUHK Direct Grant (No. 4054714), and the Key-Area R&D Program of Department of Science and Technology of Hunan Province (No. 2022WK2010). Figures were created by Biorender.
Publisher Copyright:
© 2025 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.
PY - 2025/7
Y1 - 2025/7
N2 - 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.
AB - 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.
KW - E3 ligand
KW - POI ligand
KW - artificial intelligence
KW - cancer therapy
KW - linker design
KW - proteolysis targeting chimeras (PROTACs)
UR - https://www.scopus.com/pages/publications/105011268226
U2 - 10.1002/mco2.70258
DO - 10.1002/mco2.70258
M3 - Journal article
C2 - 40567248
SN - 2688-2663
VL - 6
JO - MedComm
JF - MedComm
IS - 7
M1 - e70258
ER -
