NASH Target Development Service for Caspase Inhibitors

Nonalcoholic steatohepatitis (NASH), a potentially progressive liver disease that culminates in cirrhosis, has become a serious disease in the world. Caspases have become the potential targets because of the significant activation of caspases in the liver during NASH. Creative Biolabs is a leading service provider in the target identification for drug discovery. We can provide a full range of target screening, structural characterization, and functional profiling services for identifying potential drug targets. At present, we offer a range of target screening for NASH treatment and also develop high-quality caspase inhibitors for NASH therapeutic to meet our customers' unique specifications.

Introduction of Caspase

Caspases are a family of proteases that are primarily involved in programmed cell death and inflammation. They possess specific cysteine protease activity. So far, there are 11 or 12 confirmed caspases in humans and 10 in mice, carrying out a variety of cellular functions. The function of these enzymes in programmed cell death was first found in 1993. Activation of caspase ensures that the cellular components are degraded in a regulated manner, eliminating cell death with minimal effect on surrounding tissues. Caspases also have a critical role in inflammation, whereby they directly process pro-inflammatory cytokines such as pro-IL1β. These are signal molecules that allow the recruitment of immune cells to an infected cell or tissue. Other roles of caspases have been confirmed such as cell proliferation, tumour suppression, cell differentiation, neural development, axon guidance, and aging. All of these caspase enzymes can be subclassified into three types: initiator, executioner, and inflammatory.

Fig.1 Selected caspase activation pathways. (Cullen, 2009)

The Role of Caspase Inhibitors in NASH

Apoptosis is a programmed type of cell death that is mediated by the activation of caspases in the liver. In NASH, activation of caspases requires caspase activity. Based on this feature, it has been possible to design pan-caspase inhibitors that broadly inhibit all caspases. Such pan-caspase inhibitors not only inhibit cellular apoptosis but also block proteolytic cleavage of certain interleukin (IL) molecules, including IL-1β and IL-18. Both ILs are cleaved by caspase-1 to generate smaller, biologically active proinflammatory cytokines that have been involved in liver injury pathogenesis. Thus, pan-caspase inhibitors have been presented as the attractive therapeutic agents for many types of liver disease, including NASH.

Caspase Inhibitors for NASH Treatment

Emricasan (IDN-6556) is an irreversible pan-caspase inhibitor, which was evaluated in clinical trials for chronic liver disease. It has been granted fast track designation by the FDA for the development of NASH cirrhosis. Researches have shown that liver injury and fibrosis are suppressed by inhibiting hepatocytes apoptosis in a mouse model of NASH, which shows Emricasan is an attractive anti-fibrotic therapy in NASH.

Since the phagocytosis of apoptotic cells activates hepatic stellate cells (HSCs), another pan-caspase inhibitor, VX-166 has been developed, which can reduce the progression of fibrosis in a mouse model of NASH. Treatment of MCD-fed mice with VX-166 reduced caspase-3 activity. Besides, VX-166-treated MCD-fed mice demonstrated decreased hepatic levels of collagen 1α1 messenger RNA. Further data confirmed that VX-166-treated livers decreased in fibrosis. Therefore, blocking hepatic apoptosis can inhibit the development of fibrosis in mice with NASH. These findings are consistent with the evidence of apoptosis-induced HSC activation and liver fibrosis, suggesting that caspase inhibitors can be used as an antifibrotic NASH therapy.

Fig.2 Therapeutic agents that target hepatocyte injury and the sterile inflammatory response in NASH. (Ibrahim, 2018)

Features

• Time- and labor-saving
• Versatile screening strategies available
• Competitive price
• Skillful team and professional technical support throughout the project

With years of experience in the field of disease target development, Creative Biolabs is capable of providing unique caspase inhibitors for the NASH treatment to meet each customer's requirements. Moreover, we provide high-quality NASH-associated target construction and custom target screening services. Please feel free to contact us for more information and a formal quote.

References

1. Cullen, S.P.; Martin, S. J. Caspase activation pathways: some recent progress. Cell Death & Differentiation. 2009, 16(7): 935-938.
2. Ibrahim, S.H.; et al. Non-alcoholic steatohepatitis pathogenesis: sublethal hepatocyte injury as a driver of liver inflammation. Gut. 2018, 67(5): 963-972.