上睑下垂
炎症体
半胱氨酸蛋白酶
炎症
程序性细胞死亡
半胱氨酸蛋白酶1
细胞凋亡
医学
药理学
癌症研究
化学
免疫学
生物化学
作者
Qi Xiao,Jin‐Sheng Yu,Yufang Wang,Danjun Ma,Jian Zhou,Xin Lou
标识
DOI:10.1021/acsmedchemlett.0c00070
摘要
Dysregulation of the inflammatory response is a key driver of many debilitating and costly diseases including immune disorders, cancer, and infection. Pyroptosis is a highly inflammatory form of programmed cell death, triggered by various stimuli and meditated by the activation of inflammatory caspases. Pharmacologic agents that provide strategies to modulate pyroptosis for research and clinical practice are still very limited. In current study, we identify 3-difluoroalkyl quaternary oxindoles as chemical inhibitors of caspase-1, the pyroptosis driving caspase. Our results demonstrated compound 6 could directly bind to the CARD domain of pro-caspase-1 to inhibit its infammasome recruitment and pharmacologic inhibition of pyroptotic cell death by compound 6 is partially efficacious in sepsis models. Compound 6 is thus a potential therapeutic for inflammatory disorders and a tool for further study of the inflammation in human health and disease.
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