NASH Target Development Service for Nuclear Factor Erythroid-2 Related Factor 2 (NRF2)

Nuclear factor-erythroid-2-related factor 2 (NRF2) plays a central role in stimulating expression of various antioxidant-associated genes in the cellular defense against oxidative stress. Creative Biolabs and our collaborators have established manufacturing platforms and pipelines fully designated for electrophilic small-molecule NRF2 activators or non-electrophilic NRF2 activators and NRF2 activator manufacturing. With years of experience and high-end technologies in drug discovery, Creative Biolabs provides the world's leading target discovery services for non-alcoholic steatohepatitis (NASH) therapeutic.

Nuclear Factor Erythroid-2 Related Factor 2 (NRF2)

Nuclear factor-erythroid-2-related factor 2, a master transcription factor of cellular defense, also known as NFE2L2 or NRF2, is a transcription factor that in humans is encoded by the NFE2L2 gene. It is an oxidative stress-mediated transcription factor that upregulates antioxidant response elements (AREs)-mediated expression of antioxidant enzyme and cytoprotective proteins. NRF2 has emerged as a significant transcription factor for the induction of a variety of detoxification enzymes, biotransformation enzymes, and xenobiotic efflux transporters. Its activation is initiated by oxidative or electrophilic stress and aids in the detoxification and elimination of potentially harmful exogenous chemicals and their metabolites.

Fig.1 Role of NRF2 in common mechanisms and pathophenotypes of chronic diseases. (Cuadrado, 2018)

NRF2 and NASH

Non-alcoholic fatty liver disease (NAFLD)/NASH is characterized by insulin resistance, gluconeogenesis, inflammation, and oxidative stress. These symptoms can be linked to endoplasmic reticulum (ER) stress and dysfunction of the antioxidant response controlled by the NRF2. NASH evolves in two phases, one is progressive accumulation of fatty acids in hepatocytes, and the other is liver injury and inflammatory pathologic reactive oxygen species (ROS) formation. NRF2 activation is known to increase insulin sensitivity, reduce inflammation, improve glucose and lipid blood profiles and prevent fibrosis. Molecularly, NRF2 activates the expression of a battery of genes involved in the antioxidant response, glucose metabolism, and fatty acid oxidation, while it also downregulates the expression of de novo lipogenesis and inflammatory genes. NRF2 functions as a defense system in the development of NASH. NRF2 has recently been implicated as a new therapeutic target for the treatment and prevention of some liver disease, such as liver fibrosis, and NASH.

Fig.2 Current status of the NRF2-related diseases. (Cuadrado, 2018)

Strategy for the Treatment of NASH

NRF2 plays a central role in stimulating expression of various antioxidant-associated genes in the cellular defense against oxidative stress. Creative Biolabs now provides NRF2 activators development services through our innovative chemical compound design and development platform. The strategy of NRF2 activation is expected to present new opportunities for the treatment of NASH with hepatic fibrosis. Considering the efficacy of NRF2 activators on metabolic syndrome, they may act as potential therapeutic agents for patients at any stage of NASH as it progresses.

Experienced in drug discovery and with dedicated commitment to the scientific community, Creative Biolabs has perfected our technical pipelines in the development of different kinds of NRF2 activators. We would like to share our knowledge and passion in this field to promote the advances of science and for a better tomorrow. Please contact us for more information and a detailed quote.

Reference

1. Cuadrado, A.; et al. Transcription factor NRF2 as a therapeutic target for chronic diseases: a systems medicine approach. Pharmacological reviews. 2018, 70(2): 348-383.