Inflammatory caspases: targets for novel therapies.
This review provides an overview of the biochemistry and activation of inflammatory caspases, and focuses on their therapeutic potential as disease targets in pathologies such as sepsis, Crohn's disease, rheumatoid arthritis, traumatic brain injury and amyotrophic lateral sclerosis (ALS). We summarize the proof-of-principal evidence obtained by studies in several corresponding experimental disease models confirming the validity of strategies targeting inflammatory caspases. We discuss the use of inflammatory caspase inhibitors, such as VX-740 (Pralnacasan) and VX-765, in clinical studies for rheumatoid arthritis and osteoarthritis. Finally, we point out recent approaches identifying novel peptidomimetic or non-peptide caspase inhibitors with suitable clinical profiles.
Cornelis
Sigrid
S
Department for Molecular Biomedical Research, VIB, B9052 Ghent, Belgium.
Kersse
Kristof
K
Festjens
Nele
N
Lamkanfi
Mohamed
M
Vandenabeele
Peter
P
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000201:enzymology; D001381:Azepines / Q000494:pharmacology; D001927:Brain Diseases / Q000188:drug therapy / Q000201:enzymology; D061945:Caspase Inhibitors; D020169:Caspases / Q000737:chemistry / Q000378:metabolism; D004195:Disease Models, Animal; D015195:Drug Design; D004789:Enzyme Activation; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000201:enzymology; D007546:Isoquinolines / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000201:enzymology; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011487:Protein Conformation; D011724:Pyridazines / Q000494:pharmacology; D013329:Structure-Activity Relationship; D016896:Treatment Outcome
D000893:Anti-Inflammatory Agents; D001381:Azepines; D061945:Caspase Inhibitors; D007546:Isoquinolines; D011480:Protease Inhibitors; D011724:Pyridazines; D020169:Caspases; C476331:pralnacasan