Discovery of Norbornene as a Novel Hydrophobic Tag Applied in Protein Degradation

Xie, Shaowen; Zhan, Feiyan; Zhu, Jingjie; Sun, Yuan; Zhu, Huajian; Liu, Jie; Chen, Jian; Zhu, Zheying; Yang, Dong-Hua; Chen, Zhe-Sheng; Yao, Hong; Xu, Jinyi; Xu, Shengtao

Abstract

Hydrophobic tagging (HyT) is a potential therapeutic strategy for targeted protein degradation (TPD). Norbornene was discovered as an unprecedented hydrophobic tag in this study and was used to degrade the anaplastic lymphoma kinase (ALK) fusion protein by linking it to ALK inhibitors. The most promising degrader, Hyt-9, potently reduced ALK levels through Hsp70 and the ubiquitin−proteasome system (UPS) in vitro without compensatory upregulation of ALK. Furthermore, Hyt-9 exhibited a significant tumor-inhibiting effect in vivo with moderate oral bioavailability. More importantly, norbornene can also be used to degrade the intractable enhancer of zeste homolog 2 (EZH2) when tagged with the EZH2 inhibitor tazemetostat. Thus, the discovery of novel hydrophobic norbornene tags shows promise for the future development of TPD technology.

Citation

Xie, S., Zhan, F., Zhu, J., Sun, Y., Zhu, H., Liu, J., …Xu, S. (2023). Discovery of Norbornene as a Novel Hydrophobic Tag Applied in Protein Degradation. Angewandte Chemie International Edition, 62(13), Article e202217246. https://doi.org/10.1002/anie.202217246

• Journal Article Type: Article
• Acceptance Date: Jan 19, 2023
• Online Publication Date: Feb 8, 2023
• Publication Date: Mar 20, 2023
• Deposit Date: Feb 10, 2023
• Publicly Available Date: Feb 9, 2024
• Print ISSN: 1433-7851
• Electronic ISSN: 1521-3773
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 62
• Issue: 13
• Article Number: e202217246
• DOI: https://doi.org/10.1002/anie.202217246
• Keywords: Protein Degradation; Hydrophobic Tags; Norbornene; Anticancer; PROTACs
• Public URL: https://nottingham-repository.worktribe.com/output/16789629
• Publisher URL: https://onlinelibrary.wiley.com/doi/10.1002/anie.202217246