Lazaroids U83836E and U74389G are potent, time-dependent inhibitors of caspase-1

Caspase-1 is involved in inflammatory processes and is overactive in autoimmunity and autoinflammation. Antioxidant small molecules also play a role in the immune response by decreasing inflammation. An 84-membered library of pro- and antioxidant small molecules was screened for potential inhibitors of caspase-1. Thirteen compounds were discovered to reduce the activity of caspase-1 below 30%. The most potent inhibitors were lazaroid antioxidant molecules, U83836E (B8) and U74389G (B9), displaying apparent Ki values of 48.0 and 50.0 nm, respectively. Both demonstrated a time-dependent and reversible inhibition.