Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu, 211198, China.
Department of Organic Chemistry, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu, 211198, China.
Angew Chem Int Ed Engl. 2023 Mar 20;62(13):e202217246. doi: 10.1002/anie.202217246. Epub 2023 Feb 8.
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.
疏水标记（HyT）是一种有潜力的靶向蛋白降解（TPD）治疗策略。在这项研究中，发现了降冰片烯是一种前所未有的疏水标签，并将其与 ALK 抑制剂连接，用于降解间变性淋巴瘤激酶（ALK）融合蛋白。最有前途的降解剂 Hyt-9 通过 Hsp70 和泛素-蛋白酶体系统（UPS）在体外有力地降低了 ALK 水平，而没有补偿性地上调 ALK。此外，Hyt-9 在体内具有显著的肿瘤抑制作用，且具有中等的口服生物利用度。更重要的是，当与 EZH2 抑制剂 tazemetostat 标记时，降冰片烯也可用于降解难治性增强子结合蛋白 2（EZH2）。因此，新型疏水降冰片烯标签的发现为 TPD 技术的未来发展带来了希望。
