The NF-κB Pharmacopeia: Novel Strategies to Subdue an Intractable Target

NF-kappa B transcription factors are major drivers of tumor initiation and progression. NF-kappa B signaling is constitutively activated by genetic alterations or environmental signals in many human cancers, where it contributes to almost all hallmarks of malignancy, including sustained proliferation, cell death resistance, tumor-promoting inflammation, metabolic reprogramming, tissue invasion, angiogenesis, and metastasis. As such, the NF-kappa B pathway is an attractive therapeutic target in a broad range of human cancers, as well as in numerous non-malignant diseases. Currently, however, there is no clinically useful NF-kappa B inhibitor to treat oncological patients, owing to the preclusive, on-target toxicities of systemic NF-kappa B blockade. In this review, we discuss the principal and most promising strategies being developed to circumvent the inherent limitations of conventional I kappa B kinase (IKK)/NF-kappa B-targeting drugs, focusing on new molecules that target upstream regulators or downstream effectors of oncogenic NF-kappa B signaling, as well as agents targeting individual NF-kappa B subunits.