Unlocking the NF-kappaB Conundrum: Embracing Complexity to Achieve Specificity

Transcription factors of the nuclear factor κB (NF-κB) family are central coordinating regulators of the host defence responses to stress, injury and infection. Aberrant NF-κB activation also contributes to the pathogenesis of some of the most common current threats to global human health, including chronic inflammatory diseases, autoimmune disorders, diabetes, vascular diseases and the majority of cancers. Accordingly, the NF-κB pathway is widely considered an attractive therapeutic target in a broad range of malignant and non-malignant diseases. Yet, despite the aggressive efforts by the pharmaceutical industry to develop a specific NF-κB inhibitor, none has been clinically approved, due to the dose-limiting toxicities associated with the global suppression of NF-κB. In this review, we summarise the main strategies historically adopted to therapeutically target the NF-κB pathway with an emphasis on oncology, and some of the emerging strategies and newer agents being developed to pharmacologically inhibit this pathway.