Potential pharmacological control of the NF-κB pathway

Nuclear factor (NF)-κB governs the expression of numerous genes that are important for various cellular responses. Its activation is induced by a wide variety of stimuli including stress, cigarette smoke, viral and bacterial products, cytokines, free radicals, carcinogens and tumor promoters to name a few. Deregulation of the NF-κB pathway has been observed in and attributed to the development of a variety of human ailments including cancers, autoimmune disorders, pulmonary, cardiovascular, neurodegenerative and skin diseases. Efforts to develop modulators of NF-κB have yielded several candidates, some of which are currently in Phase I/II of clinical trials. In addition, it is now becoming apparent that several of the approved drugs being currently used also work, in part, owing to their ability to influence the NF-κB pathway. In this article, we focus on the druggable components of the NF-κB signaling system and on the recent development of novel therapeutics that target NF-κB in various diseases. Nuclear factor (NF)-κB governs the expression of numerous genes that are important for various cellular responses. Its activation is induced by a wide variety of stimuli including stress, cigarette smoke, viral and bacterial products, cytokines, free radicals, carcinogens and tumor promoters to name a few. Deregulation of the NF-κB pathway has been observed in and attributed to the development of a variety of human ailments including cancers, autoimmune disorders, pulmonary, cardiovascular, neurodegenerative and skin diseases. Efforts to develop modulators of NF-κB have yielded several candidates, some of which are currently in Phase I/II of clinical trials. In addition, it is now becoming apparent that several of the approved drugs being currently used also work, in part, owing to their ability to influence the NF-κB pathway. In this article, we focus on the druggable components of the NF-κB signaling system and on the recent development of novel therapeutics that target NF-κB in various diseases. the serine-threonine protein kinase Akt (also known as protein kinase B) mediates many of the downstream effects of PI3K and consequently has a central role in both normal and pathological signaling by the PI3K pathway. Akt phosphorylates a variety of substrates involved in the regulation of key cellular functions including cell growth and survival, glucose metabolism and protein translation. describes the first and most studied mechanism of NF-κB activation. This pathway refers to the phosphorylation IκB proteins downstream of the IKK complex (IKK1–IKK2–NEMO) in response to stimulation. a proline-directed serine-threonine kinase that was initially identified as a phosphorylating and inactivating glycogen synthase. Two isoforms, GSK3α and GSK3β, show a high degree of amino acid homology within their catalytic domains. GSK3β is involved in energy metabolism, neuronal cell development and body-pattern formation. composed of two catalytic subunits, IKK1 (also known as IKKα) and IKK2 (also known as IKKβ), and a regulatory subunit, IKKγ (also known as NEMO). There are other proteins documented to be in the IKK complex but their association seems to be context dependent. the activity of NF-κB is primarily regulated by its interaction with inhibitory IκB proteins. The IκB family includes p105, p100, IκBα, IκBβ, IκBγ, IκBɛ, IκBζ and Bcl-3 proteins. Different IκB proteins might have different affinities for individual Rel–NF-κB complexes and are regulated differently in response to stimulation. They are also expressed in a distinct tissue-dependent manner. All IκB proteins contain several ‘ankyrin repeats’, which are one of the most common protein–protein interaction motifs in nature. a kinase activated in cells downstream of both the ERK1/2 (extracellular-signal-regulated kinase) and p38 MAPK (mitogen-activated protein kinase) cascades. describes the phosphorylation of p100 by an NIK–IKK1 cascade that does not require IKK1 or IKKγ and that leads to ubiquitination followed by degradation of p100 to generate the p52–RelB dimer. a ubiquitous transcription factor that controls the expression of genes involved in a number of human physiologies. Five mammalian NF-κB family members have been identified: NF-κB1 (also called p50), NF-κB2 (also named p52), RelA (also known as p65), RelB and c-Rel. They all share a highly conserved Rel homology domain, which is responsible for their dimerization and for their ability to bind to DNA and IκB (inhibitor of NF-κB). NF-κB is usually a homodimer or heterodimer of the aforementioned subunits. The p65–p50 dimer is the most abundant form and often used as a surrogate for NF-κB. comprise a family of related enzymes that are capable of phosphorylating the 3-position hydroxyl group of the inositol ring of phosphatidylinositol. PI3Ks have been linked to an extraordinarily diverse group of cellular functions including cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. large protein complexes that degrade proteins by proteolysis. Proteins are tagged for degradation by a small protein called ubiquitin. The tagging reaction is catalyzed by enzymes called ubiquitin ligases. a genetic disorder characterized by the complete inability of the adaptive immune system to orchestrate an immunological response when challenged. This phenotype is due to the absence of major lymphocytes called T and B cells. SCID in laboratory animals is used as a means to avoid interference from the immune system under certain experimental settings.