化学
结构-活动关系
免疫
对偶(语法数字)
药理学
生物化学
免疫系统
体外
免疫学
医学
艺术
文学类
生物
作者
Ji-Long Duan,Chenchen Wang,Yinghui Yuan,Zi Hui,Hang Zhang,Nian-Dong Mao,Pengpeng Zhang,Bo Sun,Lin Jing,Zishuo Zhang,Yuan Gao,Tian Xie,Xiang‐Yang Ye
标识
DOI:10.1021/acs.jmedchem.4c00090
摘要
Histone deacetylases (HDACs) inhibitors such as vorinostat (SAHA) has been used to treat hematologic malignancies (rather than solid tumors) and have been found to suppress the JAK/STAT, a critical signal pathway for antitumor immunity, while PARP7 inhibitor RBN-2397 could activate the type I interferons (IFN-I) pathway, facilitating downstream effects such as STAT1 phosphorylation and immune activation. To elucidate whether simultaneous inhibition of these two targets could interfere with these two signal pathways, a series of pyridazinone-based PARP7/HDACs dual inhibitors have been designed, synthesized, and evaluated in vitro and in vivo experiments. Compound 9l was identified as a potent and balanced dual inhibitor for the first time, exhibiting excellent antitumor capabilities both in vitro and in vivo. This suggests that 9l can be used as a valuable tool molecule for investigating the relationship between anticancer immunity and HDAC inhibition.
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