Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China; Henan Key Laboratory of Precision Clinical Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China; Henan Key Laboratory of Precision Clinical Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Bioorg Med Chem. 2023 Mar 15;82:117237. doi: 10.1016/j.bmc.2023.117237. Epub 2023 Mar 8.
Tumor hypoxia-activated proteolysis targeting chimeras (ha-PROTACs) 9 and 10 were designed and synthesized by incorporating the hypoxia-activated leaving group (1-methyl-2-nitro-1H-imidazol-5-yl)methyl or 4‑nitrobenzyl into the structure of the cereblon (CRBN) E3 ligand of an epidermal growth factor receptor 19 deletions (EGFR-based PROTAC 8. The in vitro protein degradation assay demonstrated that 9 and 10 could effectively and selectively degrade EGFR in tumor hypoxia. Meanwhile, these two compounds showed higher potency in inhibiting cell viability and migration, as well as in promoting cells apoptosis in tumor hypoxia. Moreover, nitroreductase reductive activation assay indicated that prodrugs 9 and 10 could successfully release the active compound 8. This study confirmed the feasibility to develop ha-PROTACs to enhance the selectivity of PROTACs by caging CRBN E3 ligase ligand.
肿瘤缺氧激活蛋白水解靶向嵌合体（ha-PROTACs）9 和 10 通过将缺氧激活离去基团（1-甲基-2-硝基-1H-咪唑-5-基）甲基或 4-硝基苄基纳入表皮生长因子受体 19 缺失（基于 EGFR 的 PROTAC 8 的 cereblon（CRBN）E3 配体的结构中设计和合成。体外蛋白降解测定表明，9 和 10 可有效且选择性地降解肿瘤缺氧中的 EGFR。同时，这两种化合物在抑制细胞活力和迁移以及促进肿瘤缺氧细胞凋亡方面表现出更高的效力。此外，硝基还原酶还原激活测定表明，前药 9 和 10 可以成功释放活性化合物 8。本研究证实了通过笼状 CRBN E3 连接酶配体来开发 ha-PROTACs 以增强 PROTACs 选择性的可行性。
