TY - JOUR
T1 - VX-166
T2 - A novel potent small molecule caspase inhibitor as a potential therapy for sepsis
AU - Weber, Peter
AU - Wang, Ping
AU - Maddens, Stephane
AU - Wang, Paul S.H.
AU - Wu, Rongqian
AU - Miksa, Michael
AU - Dong, Weifeng
AU - Mortimore, Michael
AU - Golec, Julian M.C.
AU - Charlton, Peter
N1 - Funding Information:
This study was sponsored by Vertex Pharmaceuticals (Europe) Ltd. and Vertex Pharmaceuticals Inc., the parent company of Vertex Pharmaceuticals (Europe) Ltd. Vertex Pharmaceuticals (Europe) Ltd. will also finance the manuscript. Peter Weber, Paul Wang, Michael Mortimore, Julian Golec and Peter Charlton are Vertex employees and hold stocks or stock options in Vertex Pharmaceuticals Inc. Stephane Maddens is a former Vertex employee. Ping Wang has previously acted as a consultant to Vertex. Vertex Pharmaceuticals Inc. holds patents or is applying for patents related to chemical matter that is the subject of the paper. Peter Weber, Michael Mortimore and Julian Golec are listed as inventors on some of these patents.
PY - 2009/9/9
Y1 - 2009/9/9
N2 - Introduction: 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.
AB - Introduction: 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.
UR - http://www.scopus.com/inward/record.url?scp=77949892535&partnerID=8YFLogxK
U2 - 10.1186/cc8041
DO - 10.1186/cc8041
M3 - Article
C2 - 19740426
AN - SCOPUS:77949892535
SN - 1364-8535
VL - 13
JO - Critical Care
JF - Critical Care
IS - 5
M1 - R146
ER -