Home
|
Inbox
|
Search
|
View Abstract
Calpain Inhibition as Anti-Fibrotic Therapy: Discovery and Pre-Clinical Evaluation of Novel Inhibitors in Models of Lung and Liver Fibrosis
Description
.abstract img { width:300px !important; height:auto; display:block; text-align:center; margin-top:10px } .abstract { overflow-x:scroll } .abstract table { width:100%; display:block; border:hidden; border-collapse: collapse; margin-top:10px } .abstract td, th { border-top: 1px solid #ddd; padding: 4px 8px; } .abstract tbody tr:nth-child(even) td { background-color: #efefef; } .abstract a { overflow-wrap: break-word; word-wrap: break-word; }
A5747 - Calpain Inhibition as Anti-Fibrotic Therapy: Discovery and Pre-Clinical Evaluation of Novel Inhibitors in Models of Lung and Liver Fibrosis
Author Block: B. Buckman, C. J. Schaefer, K. Kossen, S. Misialek, S. R. Lim, A. Arfsten, M. Kim, C. Wong, J. X. Wang, P. Ibrahim, W. Yu, M. Fuentes, W. Robbins, K. Emayan, M. Adler, J. Nicholas, S. Yuan, J. Ma, D. Kim, D. Ruhrmund, R. Rajagopalan; Blade Therapeutics, South San Francisco, CA, United States.
RATIONALE: Several pathways have been implicated as important mediators of fibrotic disease pathogenesis, including proliferation, migration, differentiation and apoptosis. Calpains are a family of non-lysosomal intracellular calcium-dependent cysteine proteases that perform limited proteolytic cleavage in response to certain cellular signaling processes, and thereby modulate these pathways. Previous calpain inhibitors suffer from poor characteristics (sub-optimal protease selectivity, potency and ADMET characteristics). Next generation calpain inhibitors with improved properties may provide important new anti-fibrotic agents. Here, we describe best-in-class small molecule calpain inhibitors with robust anti-fibrotic activity in vivo.
METHODS: Structure-based drug design (SBDD) using calpain and off-target protein crystal structures was used to design novel inhibitors. Compounds were evaluated for calpain enzyme inhibition, selectivity against other proteases, and inhibition of endogenous calpain substrate cleavage in cells. Inhibitors were optimized for in vitro ADMET and oral exposure in preclinical species. Lead compounds were evaluated for anti-fibrotic activity in rodent models bleomycin-induced of lung fibrosis and carbon tetrachloride-induced liver fibrosis.
RESULTS: Novel inhibitors display inhibition of calpain enzyme activity and calpain activity in cells. Optimized compounds exhibit high selectivity against related cysteine proteases, high metabolic stability, and favorable pharmacokinetics in preclinical species following oral and intravenous administration. Selective calpain inhibitors show significant reduction of fibrosis in both therapeutic and prophylactic efficacy models in rodent lung (bleomycin-induced) and liver (carbon tetrachloride-induced).
CONCLUSIONS: Novel, potent, selective, orally efficacious calpain inhibitors show robust anti-fibrotic effects in preclinical models of lung and liver fibrosis. We are advancing our lead development candidates towards the clinic.
Author Block: B. Buckman, C. J. Schaefer, K. Kossen, S. Misialek, S. R. Lim, A. Arfsten, M. Kim, C. Wong, J. X. Wang, P. Ibrahim, W. Yu, M. Fuentes, W. Robbins, K. Emayan, M. Adler, J. Nicholas, S. Yuan, J. Ma, D. Kim, D. Ruhrmund, R. Rajagopalan; Blade Therapeutics, South San Francisco, CA, United States.
RATIONALE: Several pathways have been implicated as important mediators of fibrotic disease pathogenesis, including proliferation, migration, differentiation and apoptosis. Calpains are a family of non-lysosomal intracellular calcium-dependent cysteine proteases that perform limited proteolytic cleavage in response to certain cellular signaling processes, and thereby modulate these pathways. Previous calpain inhibitors suffer from poor characteristics (sub-optimal protease selectivity, potency and ADMET characteristics). Next generation calpain inhibitors with improved properties may provide important new anti-fibrotic agents. Here, we describe best-in-class small molecule calpain inhibitors with robust anti-fibrotic activity in vivo.
METHODS: Structure-based drug design (SBDD) using calpain and off-target protein crystal structures was used to design novel inhibitors. Compounds were evaluated for calpain enzyme inhibition, selectivity against other proteases, and inhibition of endogenous calpain substrate cleavage in cells. Inhibitors were optimized for in vitro ADMET and oral exposure in preclinical species. Lead compounds were evaluated for anti-fibrotic activity in rodent models bleomycin-induced of lung fibrosis and carbon tetrachloride-induced liver fibrosis.
RESULTS: Novel inhibitors display inhibition of calpain enzyme activity and calpain activity in cells. Optimized compounds exhibit high selectivity against related cysteine proteases, high metabolic stability, and favorable pharmacokinetics in preclinical species following oral and intravenous administration. Selective calpain inhibitors show significant reduction of fibrosis in both therapeutic and prophylactic efficacy models in rodent lung (bleomycin-induced) and liver (carbon tetrachloride-induced).
CONCLUSIONS: Novel, potent, selective, orally efficacious calpain inhibitors show robust anti-fibrotic effects in preclinical models of lung and liver fibrosis. We are advancing our lead development candidates towards the clinic.
|
Home
|
Inbox
|
Search
|