缺氧(环境)
前药
化学
蛋白质水解
肿瘤缺氧
癌症研究
细胞生物学
药理学
生物
生物化学
氧气
内科学
医学
酶
有机化学
放射治疗
作者
Weiyan Cheng,Shasha Li,Xueqian Wen,Siyuan Han,Suhua Wang,Wei Han,Zhizhen Song,Yueqin Wang,Xin Tian,Xiaojian Zhang
摘要
Hypoxia is a hallmark of many solid tumors, and it causes the overexpression of a variety of proteins including the epidermal growth factor receptor (EGFR). Many antitumor prodrugs have been designed to target hypoxia. Here we report the identification of a kind of hypoxia-activated proteolysis targeting chimera (ha-PROTAC) by introducing the hypoxia-activated leaving group (1-methyl-2-nitro-1H-imidazol-5-yl)methyl or 4-nitrobenzyl into the structure of an EGFRDel19-based PROTAC. Among the obtained molecules, ha-PROTAC 13 exhibits a more potent degradation activity for EGFRDel19 in hypoxia than in normoxia in HCC4006 cells. This is the first example of identifying a PROTAC to selectively act on tumors utilizing the characteristic of tumor hypoxia and provides a new approach for PROTAC development.
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