Open Access3-Difluoroalkyl Quaternary Oxindoles Inhibit Macrophage Pyroptosis by Blocking Inflammasome Recruitment of Caspase-1
Author(s) -
Qi Xiao,
JinSheng Yu,
Yufang Wang,
Dongzhu Ma,
Jian Zhou,
Xin Lou
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00070
Subject(s) - pyroptosis , inflammasome , caspase , inflammation , programmed cell death , caspase 1 , apoptosis , medicine , pharmacology , cancer research , immunology , chemistry , biochemistry
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.