VX-166

A novel potent small molecule caspase inhibitor as a potential therapy for sepsis

Peter Weber, Ping Wang, Stephane Maddens, Paul S H Wang, Rongqian Wu, Michael Miksa, Weifeng Dong, Michael Mortimore, Julian M C Golec, Peter Charlton

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numberR146
JournalCritical Care
Volume13
Issue number5
DOIs
StatePublished - Sep 9 2009
Externally publishedYes

Fingerprint

Caspase Inhibitors
Sepsis
Punctures
Ligation
Lipopolysaccharides
Therapeutics
Interleukin-1beta
Survival
Lymphocytes
Apoptosis
VX
Interleukin-18
Enzyme Assays
Septic Shock
Caspases
Endotoxins
Atrophy
Flow Cytometry
Bacteria
T-Lymphocytes

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Medicine(all)

Cite this

Weber, P., Wang, P., Maddens, S., Wang, P. S. H., Wu, R., Miksa, M., ... Charlton, P. (2009). VX-166: A novel potent small molecule caspase inhibitor as a potential therapy for sepsis. Critical Care, 13(5), [R146]. https://doi.org/10.1186/cc8041

VX-166 : A novel potent small molecule caspase inhibitor as a potential therapy for sepsis. / Weber, Peter; Wang, Ping; Maddens, Stephane; Wang, Paul S H; Wu, Rongqian; Miksa, Michael; Dong, Weifeng; Mortimore, Michael; Golec, Julian M C; Charlton, Peter.

In: Critical Care, Vol. 13, No. 5, R146, 09.09.2009.

Research output: Contribution to journalArticle

Weber, P, Wang, P, Maddens, S, Wang, PSH, Wu, R, Miksa, M, Dong, W, Mortimore, M, Golec, JMC & Charlton, P 2009, 'VX-166: A novel potent small molecule caspase inhibitor as a potential therapy for sepsis', Critical Care, vol. 13, no. 5, R146. https://doi.org/10.1186/cc8041
Weber, Peter ; Wang, Ping ; Maddens, Stephane ; Wang, Paul S H ; Wu, Rongqian ; Miksa, Michael ; Dong, Weifeng ; Mortimore, Michael ; Golec, Julian M C ; Charlton, Peter. / VX-166 : A novel potent small molecule caspase inhibitor as a potential therapy for sepsis. In: Critical Care. 2009 ; Vol. 13, No. 5.
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abstract = "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.",
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AU - Weber, Peter

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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

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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.

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