克里唑蒂尼
小脑
泛素连接酶
卡林
蛋白质降解
癌症
癌症研究
蛋白质水解
酪氨酸激酶抑制剂
药理学
医学
泛素
肺癌
生物
肿瘤科
内科学
细胞生物学
生物化学
基因
恶性胸腔积液
酶
作者
Jin-Jiao Chen,Jinmei Jin,Wenjie Gu,Zeng Zhao,Yuan Hu,Yifeng Zhou,Dale G. Nagle,Qiulei Xi,Xuemei Zhang,Qian Sun,Ye Wu,Weidong Zhang,Xin Luan
出处
期刊:Cancer Science
[Wiley]
日期:2023-02-07
卷期号:114 (5): 1958-1971
被引量:3
摘要
As one of the common malignant cancer types, gastric cancer (GC) is known for late-stage diagnosis and poor prognosis. Overexpression of the receptor tyrosine kinase MET is associated with poor prognosis among patients with advanced stage GC. However, no MET inhibitor has been used for GC treatment. Like other tyrosine kinase inhibitors that fit the "occupancy-driven" model, current MET inhibitors are prone to acquired resistance. The emerging proteolysis targeting chimera (PROTAC) strategy could overcome such limitations through direct degradation of the target proteins. In this study, we successfully transformed the MET-targeted inhibitor crizotinib into a series of PROTACs, recruiting cereblon/cullin 4A E3 ubiquitin ligase to degrade the MET proteins. The optimized lead PROTAC (PRO-6 E) effectively eliminated MET proteins in vitro and in vivo, inhibiting proliferation and motility of MET-positive GC cells. In the MKN-45 xenograft model, PRO-6 E showed pronounced antitumor efficacy with a well-tolerated dosage regimen. These results validated PRO-6 E as the first oral PROTAC for MET-dependent GC.
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