NASH Target Development Service for JNK Inhibitors

Creative Biolabs has successfully constructed a series of drug discovery platforms to provide most all-around NASH treatment services to our worldwide customers.

What is JNK?

c-Jun N-terminal kinases (JNK), belonging to mitogen-activated protein kinases (MAPKs) family, are kinases that respond to various stress stimuli, such as ultraviolet irradiation, cytokines, heat shock, ischemia, and osmotic shock. There are 10 isoforms of JNK encoded by MAPK8, MAPK9, and MAPK10: JNK1 (4 isoforms, also known as Mitogen-activated protein kinase 8, MAPK8), JNK2 (4 isoforms, also known as Mitogen-activated protein kinase 9, MAPK9), and JNK3 (2 isoforms, also known as Mitogen-activated protein kinase 10, MAPK10). JNK1 and JNK2 isoforms are expressed in all cells and tissues, whereas, JNK3 isoforms are primarily found in the brain, followed by heart and testicles.

JNK are known to regulate several transcriptional processes involved in inflammation, brain tissue injury, and cell apoptosis. It is suggested that JNK also implicated to multiple important processes and cellular responses including differentiation, proliferation, migration, and immune reaction. Moreover, JNK and related JNK signaling pathway play critical roles in many pathogeneses and disorders like nervous system disease, cancer, atherosclerosis, etc.

Fig.1 Structures of c-Jun N-terminal kinases.

JNK Inhibitors for NASH Treatment

Pharmacological studies and in vitro gene deletion have indicated that JNK and JNK signaling pathways may be key factors in the pathogenesis of nonalcoholic fatty liver disease, including nonalcoholic steatohepatitis (NASH), acute hepatocellular injury, and hepatocarcinogenesis. JNK were pointed to induce NASH not only through initial hepatic lipid accumulation (“first hit”) but also through liver injury, inflammation, and fibrosis (“second hit”). JNK overexpression or activity increasing promotes the insulin resistance and hepatic steatosis in obesity animal models and NASH patients, whereas JNK deletion or inhibition alleviates hepatic steatosis. However, only liver specific JNK1 deletion improves hepatic steatosis and significantly increases circulating triglycerides levels. In addition, JNK promote hepatic inflammation by activating the transcription of pro-inflammatory cytokines through the activator protein-1 (AP-1), where the process also associates with nuclear factor-κB, caspase-8, cytochrome C, etc. Importantly, researches on high-fat diet mice revealed that different JNK isoforms exerted distinct effects on NASH. JNK1 may aggravate hepatitis and steatosis whereas JNK2 may prevent against hepatocyte cell death.

Based on existing investigations, we found that JNK may be the lipotoxic targets and have great potential for NASH treatment. It is worth noting that JNK1 isoform inhibitors can serve as effective NASH therapeutic candidates, and JNK2 isoform activators will play a synergistic role in NASH treatment.

Fig.2 Multiple roles of JNK isoforms in the pathogenesis of nonalcoholic fatty liver disease. (Kodama, 2009)

Equipped with well-constructed platforms (e.g. Hit to Lead, Lead Optimization, IND-Enabling, Target Identification, and Validation, Hit identification) as well as years of efforts and experiences, Creative Biolabs is proud to offer our global clients with the best and comprehensive NASH treatment services. In addition, our seasoned scientists can provide customized solutions for your NASH treatment projects. Just feel free to contact us or send us an inquiry and tell us your needs.

Reference

1. Kodama, Y.; Brenner, D.A. c-Jun N-terminal kinase signaling in the pathogenesis of nonalcoholic fatty liver disease: Multiple roles in multiple steps. Hepatology. 2009, 49(1): 6-8.