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

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. A novel norbornene‐based hydrophobic tag was developed that expands the clinical potential of targeted protein degradation technologies. The degrader Hyt‐9, which was obtained by connecting an ALK ligand with norbornene, exhibited potent antiproliferative and degradative activities in vitro and in vivo. Furthermore, norbornene could be used to degrade EZH2 when tagged with the EZH2 inhibitor tazemetostat in degrader Hyt‐13.