NF-κB in Human Disease: Current Inhibitors and Prospects for De Novo Structure Based Design of Inhibitors

Abstract

Nuclear-Factor kappa B (NF-kappaB) is an inducible transcription factor of the Rel family, sequestered in the cytoplasm by the IkappaB family of proteins. NF-kappaB exists in several dimeric forms, but the p50/p65 heterodimer is the predominant one. Activation of NF-kappaB by a range of physical, chemical, and biological stimuli leads to phosphorylation and proteasome dependent degradation of IkappaB, leading to the release of free NF-kappaB. This free NF-kappaB then binds to its target sites (kappaB sites in the DNA), to initiate transcription. This transcription has been known to be involved in a number of diseases including cancer, AIDS, and inflammatory disorders. The present article focuses on two important issues of current and future interest- firstly a review of the main human diseases which are initiated due to NF-kappaB mediated transcription is presented. Next, comprehensive information on the current inhibitors which are targeted to interfere with the NF-kappaB pathway is provided. This latter section presents a critical review on different types of latest inhibitors targeting the complex NF-kappaB pathway at several stages. The inhibitors developed till date and still under investigation, include mainly those which interfere with the activation of NF-kappaB. Based on the complexity of NF-kappaB activation, and the current knowledge of the structural biology of NF-kappaB-DNA binding, finally it is proposed that a better approach to inhibit NF-kappaB induced transcription exists. In this context, a perspective is presented in the end, proposing de novo design of inhibitors which directly interact with the DNA Binding region of the free NF-kappaB (p50 subunit), so as to generate more specific and selective leads of NF-kappaB-DNA binding.

Novel p65 Binding Glucocorticoid-induced Leucine Zipper Peptide Suppresses Experimental Autoimmune Encephalomyelitis

“…Targeted inhibition of the NF-B complex is an actively investigated strategy to control inflammation (16). Previous approaches include interference with DNA binding by decoy nucleotides, blocking nuclear translocation by NF-B dimers, inhibiting signaling kinases, and use of proteasome inhibitors (45). The NF-B subunits also interact with multiple transcriptional regulators of cellular proliferation and apoptosis (45).…”

Inhibitors of NF-κB signaling: 785 and counting

“…ATP analogs include natural products such as b-carboline, and several synthetic compounds developed by pharmaceutical companies, such as SC-839, which has an approximately 200-fold preference for IKKb as compared to IKKa (reviewed in Karin et al, 2004;Pande and Ramos, 2005). On the other hand, the synthetic compound BMS-345541 binds to an allosteric site on both kinases, but shows an approximately 10-fold greater inhibitory effect on IKKb (Burke et al, 2003).…”

Gallic Acid Suppresses Lipopolysaccharide-Induced Nuclear Factor-κB Signaling by Preventing RelA Acetylation in A549 Lung Cancer Cells

“…Given the ubiquitous expression of NF-κB and the important number of inducing stimuli and target genes, it is not surprising that NF-κB is involved in numerous and diverse diseases (14)(15)(16). Therefore, NF-κB may be a therapeutic target for pharmaceutics that interfere with the establishment and the progression of these pathologic states (17).…”