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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


Shaowen Xie

Feiyan Zhan

Jingjie Zhu

Yuan Sun

Huajian Zhu

Jie Liu

Associate Professor

Associate Professor in International Pharmacy and Traditional Medicines

Dong-Hua Yang

Zhe-Sheng Chen

Hong Yao

Jinyi Xu

Shengtao Xu


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.

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
Keywords Protein Degradation; Hydrophobic Tags; Norbornene; Anticancer; PROTACs
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