NASH Target Development Service for Endothelin-A Receptor

Endothelin-A receptor has been shown to be involved in hepatic fibrosis, and its antagonists are effective in alleviating the progression of hepatic fibrosis in nonalcoholic steatohepatitis (NASH) and therefore have great potential for the treatment of NASH. With extensive experience and a high-end platform, Creative Biolabs offers synthesis services for a comprehensive range of small molecule antagonists, including ET-A receptor antagonists, which opens up new ideas for early treatment of NASH.

Introduction of Endothelin-A Receptor

The endothelin (ET)-1 is one of the most potent vasoconstrictors and mitogenic peptides in the body and exerts its physiological functions through binding to specific receptors: ET-A and ET-B. ET-A mainly acts on the vascular system, leading to vasoconstriction. ET-1 can contribute to the development and progression of inflammation and fibrosis and vascular remodeling in the kidneys and liver. The pathophysiological effects of ET-1 are mainly mediated by ET-A subtype. Studies have shown increased levels of ET-1 in plasma and tissue samples from patients with various solid tumors and upregulation of ET-A receptor (ETAR) in epithelial cancer, suggesting that ET-1 may be involved in tumor cell invasion, survival and metastasis via the ET-1/ET-A receptor axis. Since ET-1 functions by activating ET-A receptors and ETAR antagonists can compete with ET-1 to specifically bind ET-A receptor and block biological interactions between ET-1 and ET-A receptor. Therefore, antagonists of the ET-A receptor can serve as good candidates for the treatment of diseases caused by ET-1, such as cancer.

Fig.1 Schematic diagram showing the signaling mechanisms contributing to the profibrotic actions of ET-1. (Rodríguez-Pascual, 2014)

Endothelin-A Receptor for NASH Treatment

ET-1 has been shown to activate focal adhesion kinase (FAK) and integrin-linked kinase (ILK), which are the cell adhesion protein kinases known to receive influences from the extracellular matrix (ECM) via integrins. In NASH, the serum ET-1 levels are elevated and associated with hepatic fibrosis severity. The development of hepatic fibrosis is largely mediated by activation of hepatic stellate cells (HSCs). When ET-1 is released from sinusoidal endothelial cells and HSCs, it binds to ET-A receptor to induce contraction, proliferation and collagen synthesis of HSCs and activate HSCs, leading to the progression of liver fibrosis. In addition, ET-1 may also increase the inflow of free fatty acids from the fat tissue into the liver and exacerbate hepatic steatosis. Therefore, ET-1 antagonism may be a novel target for steatohepatitis. Ambrisentan is an ET-A receptor antagonist that reduces liver fibrosis by inhibiting HSCs activation without affecting hepatic steatosis in a mouse model of NASH. ET-A receptor antagonist significantly attenuated the progression of hepatic fibrosis and provide new strategies for the treatment of NASH.

In addition to NASH-related services, we also provide drug discovery (including Hit to Lead, Lead Optimization, IND-Enabling, Target Identification and Validation, Hit identification) and antibody development services (including Phage Display & Antibody Library Services, Antibody Analysis Services, Antibody Engineering Services) based on other diseases. Our service platform is a cost-effective and effective option for you to accelerate the development of drug targets. If you would like more information, please contact us.

Reference

1. Rodríguez-Pascual, F.; et al. The profibrotic role of endothelin-1: is the door still open for the treatment of fibrotic diseases? Life sciences. 2014, 118(2): 156-164.