NF-κB Signaling and Inflammation—Drug Repurposing to Treat Inflammatory Disorders?

SIMPLE SUMMARY: Since its first description 35 years ago, the transcription factor NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) has been shown to be a key mediator of immune cell responses to inflammatory mediators, oxidative stress and genotoxic injury. Dysregulated NF-κB signalling drives inflammation in inflammatory disorders such as multiple sclerosis, rheumatoid arthritis or inflammatory bowel disease. Thus, re-establishing the appropriate regulation of NF-κB activity seems like a promising approach to treat inflammatory diseases. Current anti-inflammatory drugs have many, often serious, side effects. Thus, there is an unmet clinical need for safe and effective anti-inflammatory medicines that both decrease inflammatory mediator production and enhance endogenous anti-inflammatory and prorepair pathways. So far, traditional de novo drug discovery has fallen short of satisfying this need. Drug repurposing is a cost- and time-effective alternative to de novo drug development for the identification of novel applications and has already resulted in the identification of effective anti-inflammatories in the ongoing COVID-19 pandemic. In this paper we critically review NF-κB as a potential target for the development of anti-inflammatory drugs with an emphasis on drug repurposing as a strategy to identify new approaches to treat inflammatory diseases. ABSTRACT: NF-κB is a central mediator of inflammation, response to DNA damage and oxidative stress. As a result of its central role in so many important cellular processes, NF-κB dysregulation has been implicated in the pathology of important human diseases. NF-κB activation causes inappropriate inflammatory responses in diseases including rheumatoid arthritis (RA) and multiple sclerosis (MS). Thus, modulation of NF-κB signaling is being widely investigated as an approach to treat chronic inflammatory diseases, autoimmunity and cancer. The emergence of COVID-19 in late 2019, the subsequent pandemic and the huge clinical burden of patients with life-threatening SARS-CoV-2 pneumonia led to a massive scramble to repurpose existing medicines to treat lung inflammation in a wide range of healthcare systems. These efforts continue and have proven to be controversial. Drug repurposing strategies are a promising alternative to de novo drug development, as they minimize drug development timelines and reduce the risk of failure due to unexpected side effects. Different experimental approaches have been applied to identify existing medicines which inhibit NF-κB that could be repurposed as anti-inflammatory drugs.