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Drugs targeting transcription factor NRF2 developed for many chronic diseases

The transcription factor NRF2 and the regulatory protein KEAP1 that inhibits its function are key regulators of inflammation and oxidative stress in cells, and thus targets of intensive drug research. The mechanisms, uses and challenges of new drugs targeting this regulatory system were recently reported in an extensive review by an international consortium.

Published in Nature Reviews in Drug Discovery, the authors of the review article include the field’s leading scientists from universities and pharmaceutical companies around the world, with Professor Anna-Liisa Levonen from the A.I. Virtanen Institute for Molecular Sciences at the University of Eastern Finland among them.

The NRF2 transcription factor regulates hundreds of genes whose function plays a role in, for example, drug metabolism, antioxidant defence, carbohydrate and lipid metabolism, and regulation of inflammatory functions. Due its wide range of effects, this transcription factor has not traditionally been regarded as a particularly lucrative target molecule by the pharmaceutical industry. However, thanks to advances made in academic research and in the development of certain drugs that activate NRF2, the situation is starting to change. The first drug impacting on the NRF2-KEAP1 regulatory system, dimethyl fumarate, was approved for the treatment of multiple sclerosis in 2013. Having been proven successful, many other drugs have since proceeded to clinical trials. For instance, bardoxolone methyl is being studied as a treatment for rare kidney diseases, and sulforaphane for type 2 diabetes.

The review article presents a summary of drugs that have proceeded to clinical trials, as well as of new, preclinical-phase molecules and their mechanisms in the treatment of, e.g., pulmonary diseases, neurodegenerative diseases, metabolic disorders and complications of diabetes. The review also analyses the challenges of drug development.

“Uncontrolled overactivity of NRF2 has been associated with certain cancers, and although there aren’t any indications from clinical trials that drugs activating the NRF2 transcription factor would increase the risk of cancer, this is nevertheless something we have to keep in mind,” Professor Levonen says.

“Despite the challenges, drugs affecting the NRF2-KEAP1 regulatory system provide a multi-target effect that inhibits inflammation and protects cells, and this is particularly well suited for the treatment of degenerative diseases associated with oxidative stress.”

For further information, please contact:

Professor Anna-Liisa Levonen, anna-liisa.levonen (a) uef.fi; tel. +358 40 358 9907

Article:

Antonio Cuadrado, Ana I. Rojo, Geoffrey Wells, John D. Hayes, Sharon P. Cousin, William L. Rumsey5, Otis C. Attucks, Stephen Franklin, Anna-Liisa Levonen, Thomas W. Kensler & Albena T. Dinkova-Kostova. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nature Reviews Drug Discovery (2019). Published 4 January 2019. https://www.nature.com/articles/s41573-018-0008-x