NASH Target Development Service for MAP Kinases Inhibitors

There is no pharmacological therapy approved for the treatment of non-alcoholic steatohepatitis (NASH). In the liver, mitogen-activated protein (MAP) kinases play a key role in the regulation of metabolic processes and may become a novel target for NASH treatment. As a famous expert in the world, Creative Biolabs has strong ability in drug discovery, structural characterization, and functional profiling for identifying potential molecular targets. And we can offer a series of comprehensive service packages and corresponding clinical trials for NASH therapeutics.

MAP Kinases Inhibitors

The MAP kinases are prevalent regulators of many cellular functions, involving cell growth, proliferation, differentiation, and certain inflammatory responses. The MAP kinase family contains four major members based on sequence similarity: the extracellular signal-regulated kinases-1 and 2 (ERK1 and ERK2), the c-Jun N-terminal kinases (JNK), p38 MAP kinases (p38 MAPK), and Big MAP kinase-1 (BMK1/ERK5). Each of MAP kinases is activated by highly specific interactions with upstream MAP or ERK kinases. Once activated, MAP kinases, in turn, phosphorylate and regulate substrates including transcription factors, translation regulators, structural proteins, other kinases, and signaling proteins. Considering their roles in proliferative diseases or inflammatory disorders, a number of pharmacological inhibitors have been developed to block MAP kinase signaling pathways.

Tab.1 Pharmacological inhibitors of MAP kinases and proteins that regulate MAP kinase signaling pathways. (Burkhard, 2010)

MAP Kinases Inhibitors in NASH

The MAP kinases participate in an array of processes that control hepatic metabolism and their concerted activities cause the phosphorylation of downstream targets. The liver regulates lipid metabolism and glucose homeostasis and occurs to dysfunction under conditions such as obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic fatty liver disease (NAFLD). And NAFLD is subsequently accompanied by hepatic inflammation leading to NASH.

Fig.1 Growth factor receptors, cytokine receptors, and free fatty acids can stimulate the activities of ERK, JNK, and p38 MAPK in the liver. (Lawan, 2017)

Mouse models deficiency in MAP kinases (ERKs, JNK, and p38 MAPK) reveal a variety of liver-associated metabolic defects that result either directly or indirectly from the loss of these MAP kinases. The obesity and related inflammatory state in insulin-responsive tissues can activate stress-responsive MAP kinases, ERKs, JNK, and p38 MAPK, which have been prominently figured as critical effectors of pathophysiological hepatic metabolism. Given the influence that constitutive activation of MAP kinases in NASH, relevant inhibitors are studied to block MAP kinases signals. The inhibitors target multiple proteins in the signaling cascades stemming from the plasma membrane receptors to the specific MAP kinase. The ability of inhibitors to manipulate the MAP kinase signaling cascades is particularly valuable for understanding mechanisms that modulate cell functions and for improving clinical therapies on NASH diseases.

MAP Kinases Inhibitors Development at Creative Biolabs

To realize the underlying principles that govern the progressions of hepatosteatosis to NASH plays a vital part in identifying new modalities of therapeutic intervention. Tailoring pharmacotherapy to the dominant pathogenic pathway is likely to represent the future direction in patients with NASH. Creative Biolabs is one of the well-recognized institutes in disease target development for a wide range of projects, who can offer superior target construction, characterization (physical, chemical, and characters), and analysis services to satisfy clients’ demands. Remarkably, we have already launched the following small molecule development strategies for novel MAP kinases inhibitors, including Hit to Lead, Target Identification and Validation, Lead Optimization, and many others.

Furthermore, additional methods to inhibit MAP kinase pathways in treating diseases include monoclonal antibodies against extracellular domains or ligands of receptor tyrosine kinases. As a specialist in the antibody field, Creative Biolabs also could share and introduce our powerful antibody development platforms: Phage Display & Antibody Library Services, Antibody Analysis Services, and Antibody Engineering Services. If you are interested in our services, please contact us for more information.

References

1. Burkhard, K.; et al. Use of inhibitors in the study of MAP kinases. Methods Mol Biol. 2010, 661: 107-122.
2. Lawan, A.; et al. Mitogen-Activated Protein Kinase Regulation in Hepatic Metabolism. Trends Endocrinol Metab. 2017, 28(12): 868-878.