3‑Difluoroalkyl Quaternary Oxindoles Inhibit Macrophage Pyroptosis by Blocking Inflammasome Recruitment of Caspase‑1

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.