Lazaroids U83836E and U74389G are Potent, Time-Dependent Inhibitors of Caspase-1

• Published in: Chemical biology & drug design Vol. 86; no. 5; pp. 1049 - 1054
• Main Authors: Kawarski, Margaret, Hagerman, Thomas K., Karver, Caitlin E.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.11.2015
• Subjects: antioxidants; Antioxidants - chemistry; Antioxidants - pharmacology; Caspase 1 - metabolism; Caspase Inhibitors - chemistry; Caspase Inhibitors - pharmacology; caspase-1; Drug Discovery; Humans; inhibitors; lazaroids; library screening; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; inhibitors; antioxidants; caspase-1; library screening; lazaroids
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.12572

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. Caspase‐1 undergoes potent and time‐dependent inhibition using the antioxidant lazaroids U83836E and U74389G. Both lazaroids inhibited caspase‐1 with Ki values near 50 nm and were readily reversed to regenerate active caspase‐1. These studies provide a link between antioxidants and caspase‐1 inhibition for the potential treatment of inflammatory disorders.