癌症研究
内质网
激活剂(遗传学)
细胞生物学
生物
细胞培养
化学
受体
生物化学
遗传学
作者
Pengyu Wang,Tao Zhang,Xinjing Wang,Hongying Xiao,Huiti Li,Lingsha Zhou,Teng Yang,Bingyan Wei,Zeyun Zhu,Lu Zhou,Yang Song,Xiang Lü,Yonghui Zhang,Yue Huang,Jianhua Gan,Cai‐Guang Yang
标识
DOI:10.1016/j.chembiol.2022.07.002
摘要
The mitochondrial caseinolytic protease P (ClpP) is a target candidate for treating leukemia; however, the effects of ClpP modulation on solid tumors have not been adequately explored. Here, we report a potent activator of ClpP with the therapeutic potential for pancreatic ductal adenocarcinoma (PDAC). We first validated that aberrant ClpP activation leads to growth arrest of PDAC cells and tumors. We then performed high-throughput screening and synthetic optimization, from which we identified ZG111, a potent activator of ClpP. ZG111 binds to ClpP and promotes the ClpP-mediated degradation of respiratory chain complexes. This degradation activates the JNK/c-Jun pathway, induces the endoplasmic reticulum stress response, and consequently causes the growth arrest of PDAC cells. ZG111 also produces inhibitory effects on tumor growth in cell line-derived and patient-derived xenograft mouse models. Altogether, our data demonstrate a promising therapeutic strategy for PDAC suppression through the chemical activation of ClpP.
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