A critical role for persistent inflammation in the pathogenesis of multiple diseases with diverse clinical manifestations such as the immune mediated rheumatoid arthritis (RA)/multiple sclerosis (MS) or the neurodegenerative Alzheimer’s disease (AD)/Parkinson’s disease (PD) is currently well recognized 1-5 . Sustained or unregulated activation of the transcription factor, nuclear factor kappa B (NF-) is integral to the persistence of inflammation 6, 7. The term NF-B includes five structurally related and evolutionarily conserved rel proteins: RelA (p65), RelB, c-Rel (REL), NF-B1 (p50 and its precursor p105), and NF-B2 (p52 and its precursor p100) 2. In resting cells, NF- exists in the cytoplasm in several dimeric forms bound to I inhibitory proteins8. NF-B signaling can be activated via the canonical or alternative pathways. Activation of NF-B via the canonical pathway mediated by microbial products or cytokines such as tumor necrosis factor-alpha (TNF- induces proteolytic degradation of the IB inhibitory proteins releasing the p50:p65subunits. p65 is the functionally dominant subunit which upon release from the inhibitory complex translocates to the nucleus, where it binds cognate NF-B binding sites in the DNA and modulates expression of several genes involved in apoptosis, immune and inflammatory responses. The NF-B signaling by alternative pathway is primarily stimulated by ligation of TNF family of receptors, involves RelB activation and modulation of genes related to cell division, differentiation and survival2, 7.
Mechanistically many drugs used in the treatment of chronic inflammatory pathologies act at least in part by inhibiting NF-B transactivation. For example, the effects of many of the non-steroidal anti-inflammatory drugs (NSAID) are mediated by suppression of NF-B activation by inhibiting IKK complex or by activation of peroxisome proliferation-activated receptor PPAR-γ, a negative regulator of NF-B transcription2, 9. The profound anti-inflammatory potential of the widely used glucocorticoids is largely attributed to the inhibition of p65 induced transactivation of inflammatory genes10. Furthermore, targeting NF-B activation is one of the mechanisms of action of many currently approved biologics. The efficacies of anti-TNF-treatment11 or of abatacept, a T cell costimulatory antagonist in RA12 or that of glatiramer acetate in MS13 are associated with indirect inhibition of NF-B signaling. However non-specific responses, serious adverse effects and/or high cost are some of the factors that compromise the long-term use of these therapeutic agents. Hence development of potent and selective inhibitors of the NF-B canonical signaling pathway for inflammation associated chronic pathologies constitute an important goal of many researchers and pharmaceutical companies involved in drug discovery.