title: VX-166: a novel potent small molecule caspase inhibitor as a potential therapy for sepsis.
abstract: BACKGROUND
  Prevention of lymphocyte apoptosis by caspase inhibition has been proposed as a novel treatment approach in sepsis. However, it has not been clearly demonstrated that caspase inhibitors improve survival in sepsis models when dosed post-insult. Also, there are concerns that caspase inhibitors might suppress the immune response. Here we characterize VX-166, a broad caspase inhibitor, as a novel potential treatment for sepsis.
  
  
  METHODS
  VX-166 was studied in a number of enzymatic and cellular assays. The compound was then tested in a murine model of endotoxic shock (lipopolysaccharide (LPS), 20 mg/kg IV) and a 10 d rat model of polymicrobial sepsis by caecal ligation and puncture (CLP).
  
  
  RESULTS
  VX-166 showed potent anti-apoptotic activity in vitro and inhibited the release of interleukin (IL)-1beta and IL-18. In the LPS model, VX-166 administered 0, 4, 8 and 12 h post-LPS significantly improved survival in a dose-dependent fashion (P < 0.0028). In the CLP model, VX-166 continuously administered by mini-osmotic pump significantly improved survival when dosed 3 h after insult, (40% to 92%, P = 0.009). When dosed 8 h post-CLP, VX-166 improved survival from 40% to 66% (P = 0.19). Mode of action studies in the CLP model confirmed that VX-166 significantly inhibited thymic atrophy and lymphocyte apoptosis as determined by flow cytometry (P < 0.01). VX-166 reduced plasma endotoxin levels (P < 0.05), suggesting an improved clearance of bacteria from the bloodstream. Release of IL-1beta in vivo or T-cell activation in vitro were moderately affected.
  
  
  CONCLUSIONS
  Our studies enhance the case for the use of caspase inhibitors in sepsis. VX-166 itself has promise as a therapy for the treatment of sepsis in man.
authors.affiliation: Biology Department, Vertex Pharmaceuticals Europe Limited, Abingdon OX14 4RY, UK. peter_weber@vrtx.com
authors.forename: Peter
authors.initials: P
authors.lastname: Weber
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Stephane
authors.initials: S
authors.lastname: Maddens
authors.forename: Paul Sh
authors.initials: PSh
authors.lastname: Wang
authors.forename: Rongqian
authors.initials: R
authors.lastname: Wu
authors.forename: Michael
authors.initials: M
authors.lastname: Miksa
authors.forename: Weifeng
authors.initials: W
authors.lastname: Dong
authors.forename: Michael
authors.initials: M
authors.lastname: Mortimore
authors.forename: Julian M C
authors.initials: JM
authors.lastname: Golec
authors.forename: Peter
authors.initials: P
authors.lastname: Charlton
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D061945:Caspase Inhibitors; D020169:Caspases / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D008297:Male; D051379:Mice; D023421:Models, Animal; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000188:drug therapy* / Q000503:physiopathology; D013534:Survival; D016896:Treatment Outcome
chemical_list: D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D020169:Caspases