NASH Target Development Service for ERK Inhibitors

Nonalcoholic steatohepatitis (NASH) is a serious form of the disease, characterized by liver inflammation, which may progress to scarring and irreversible damage. Currently, no specific medical therapy has been found effective in NASH. Extracellular signal-regulated kinases (ERKs) are the important factors during the NASH that can be thought of as a potential target for this disease therapy. As a long-term expert in target identification for drug discovery, Creative Biolabs owns lots of scientists who are proficient in target screening, structural characterization, and functional profiling services for identifying potential drug targets. Our professional scientists are pleased to provide high-quality ERK inhibitors for NASH therapeutic.

Introduction of ERK

Extracellular-signal-regulated kinases (ERKs) represent a larger family of mitogen-activated protein (MAP) kinases including the ERKs (ERK1, ERK2, ERK3/4, ERK5, ERK7), the c-JunNH2-terminal kinases (JNKs) and the p38 MAP kinases. ERKs are involved in both vasoconstriction and vascular smooth muscle cell growth. Although other isozymes of ERK are known, ERK1 and ERK2 are the most studied. They retain 84% identical and share many functions. Phosphorylated ERK1 and ERK2 enter the nucleus, where they themselves phosphorylate transcription factors involved in cell cycle and tissue proliferation regulation. The activation of ERK1/2 cascade is initiated mainly at membrane receptors, such as receptor tyrosine kinase (RTK), G protein coupled receptor (GPCRS), ion channels, etc. ERK1/2 can regulate cell cycle progression, proliferation, cytokinesis, transcription, differentiation, senescence, cell death, migration, GAP junction formation, actin and microtubule networks, neurite extension and cell adhesion. Physiologically, ERK1/2 is essential for immune system development, homeostasis, and antigen activation, memory formation, heart development, and the response to many hormones, growth factors and insulin.

Fig.1 Organisation and function of extracellular signal-regulated kinase (ERK) pathway. (Agnoletto, 2008)

ERK Inhibitors for NASH Treatment

Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease worldwide with the character of liver inflammation. To suppress the production of pro‑inflammatory cytokines through NK-κB and ERK pathways may be a novel treatment strategy for NASH. ERK belongs to downstream mediators of leptin signaling, and it has been shown that leptin plays a crucial role in hepatic lipid regulation. The Ras→Raf→MEK(mitogen-activated kinase)→ERK signaling pathway is one of at least five MAPK pathways that modulate several fundamental cellular processes, driving proliferation, differentiation, and cell survival. Moreover, hepatic sortilin 1 (Sort1), a cellular trafficking receptor, is a novel regulator of plasma lipid metabolism and reduces plasma cholesterol and triglycerides by inhibiting hepatic apolipoprotein B production. Mechanistic studies showed that the activation of ERK can inhibit Sort1 protein by mechanisms involving Sort1 protein ubiquitination and degradation.

Therefore, some of the prominent small molecule inhibitors of the ERK pathway have been presented, those inhibitors that target proteins upstream of ERK1/2, specifically Raf and MEK1/2, which is the direct inhibition of ERK1/2 through targeting either the ATP-binding site or the surface of ERK and blocking its protein-protein interactions with its substrates. Indirect Inhibition of ERK includes the Raf inhibitors, MEK1/2 inhibitors, ATP-competitive inhibitors and non-ATP-competitive inhibitors which have exhibited a greater improvement in disease treatment.

Fig.2 ATP-competitive ERK1/2 inhibitors. (Yap, 2011)

Based on years of extensive experience in disease target discovery and development, Creative Biolabs can offer a full range of high-quality target construction and custom target screening services for NASH treatment. With the help of our professional scientists, we are confident in providing unique ERK inhibitors to meet every customer's requirements. If you have any special needs in NASH services, please feel free to contact us for more details.

References

1. Agnoletto, L. Effects of oxysterols on cell survival and proliferation pathways in human endothelial cells. 2008.
2. Yap, J.L.; et al. Small-Molecule Inhibitors of the ERK Signaling Pathway: Towards Novel Anticancer Therapeutics. ChemMedChem. 2011, 6(1): 38-48.