NASH Target Development Service for Apoptosis Signal-Regulating Kinase-1 (ASK-1) Inhibitors

Inhibition of apoptosis signal-regulating kinase 1, a serine/threonine kinase, results in improvement in inflammation and fibrosis in animal models of nonalcoholic steatohepatitis (NASH). As an acknowledged leader of target identification for drug discovery service provider, Creative Biolabs can offer high-quality development service of apoptosis signal-regulating kinase-1 (ASK-1) inhibitors for NASH therapeutic to your research and projects successfully. Our professional technical scientists can not only save your valuable time but also provide highly qualified products for our clients all over the world.

Introduction of ASK-1

Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase (MAP3K) that plays a central role in cytokine- and stress-induced apoptosis by activating c-Jun N-terminal kinase (JNK) and p38 signaling cascades. Besides, ASK1 can also enhance apoptosis when expressed in certain cell lines. ASK1 is activated in vivo by tumor necrosis factor (TNF) and Fas. The mechanism of ASK1 activation by TNF is that it could physically associate with adapter polypeptides that transduce signals from TNF receptor 1 (TNFR1). Thus, the carboxyl-terminal noncatalytic domain of ASK1 has been shown to interact with TNF receptor-associated factor 2 (TRAF2) in vivo, an adapter protein that is essential for coupling TNFR1 to the SAPKs. ASK1 can also interact with TRAF5 and 6, additional TRAFs participated in the regulation of the SAPKs by members of the TNF superfamily. ASK1 has also been shown to be activated by death-associated protein (Daxx), an adapter protein originally thought to relay signals from Fas to the SAPKs. Some studies definitely observed that Daxx can activate both ASK1 and the SAPKs.

Fig.1 Proposed model of ASK1 autoregulatory scaffolding. (Weijman, 2017)

ASK-1 Inhibitors for NASH Treatment

Hepatocytes are associated with the activation of apoptosis-related pathways, representing a hallmark of NASH and fibrosis progression. ASK1 is a ubiquitously expressed serine/threonine kinase that can be activated by oxidative stress and leading to phosphorylation of p38 mitogen-activated kinase and JNK, resulting in the activation of stress response pathways that aggravated hepatic inflammation, apoptosis, and fibrosis. Thus, inhibition of ASK1 has been believed as a target for the treatment of NASH. To date, selonsertib (formerly GS-4997) is a typical inhibitor of ASK1, significantly improved not only metabolic parameters involved in NASH but also reduced hepatic steatosis, inflammation, and fibrosis in a murine model of NASH.

In addition, ASK1 inhibitors combining with other strategies also achieved significant curative effect. For example, the simtuzumab, a humanized monoclonal antibody, directed against lysyl oxidase-like molecule 2, an enzyme that catalyzes the crosslinkage of collagen and elastin, resulting in remodeling of the extracellular matrix. Current study suggested that inhibition of lysyl oxidase-like molecule 2 with simtuzumab could have an antifibrotic effect in NASH. More importantly, preclinical data from a murine model of advanced fibrosis suggested that simtuzumab has an additive effect when combined with an ASK1 inhibitor.

Fig.2 Mechanism of targeting hepatic ASK1 to improve hepatic steatosis. (Xiang, 2016)

Features

• Experienced technical and support teams
• State-of-the-art facilities
• Specialized in target development
• Fast turnover time and competitive pricing
• Quickly and economically deliver

Creative Biolabs has long-term devoted to the disease target discovery and development. At present, we provide high-quality target construction and custom target screening services. As we have finished lots of projects based on our extensive experience, we are therefore confident in offering the best services and products for our customers all over the world. If you are interested in our services, please do not hesitate to contact us for more details.

References

1. Weijman, J.F.; et al. Structural basis of autoregulatory scaffolding by apoptosis signal-regulating kinase 1. Proceedings of the National Academy of Sciences. 2017, 114(11): E2096-E2105.
2. Xiang, M.; et al. Targeting hepatic TRAF1-ASK1 signaling to improve inflammation, insulin resistance, and hepatic steatosis. Journal of hepatology. 2016, 64(6): 1365-1377.