Design of small molecules targeting transcriptional activation by NF-κB: overview of recent advances

Abstract

Background: The transcription factor NF-κB plays a central role in immune signaling and the inflammatory response. It also activates transcription of antiapoptotic factors in tumor cells, leading to enhanced cell survival. Because of the importance of NF-κB in inflammation and cancer, there is considerable interest in development of drugs that inhibit NF-κB activation or NF-κB-directed transcription. Recent elucidation of the intracellular pathways that activate NF-κB and mechanisms for transcriptional regulation by NF-κB has identified molecular targets for rational design of such drugs. Objective: This review provides an update on NF-κB signaling and an overview of three classes of NF-κB inhibitors: i) inhibitors of IκB kinase-β (also called IKK2), an essential link in the inflammatory response; ii) agents that react with NF-κB and prevent its binding to DNA; and iii) ligands for nuclear receptors such as the glucocorticoid receptor, PPARs and liver X receptor, which interfere with NF-κB-mediated transcription through a mechanism termed ligand-dependent transrepression. Recent progress in development of glucocorticoid receptor, PPAR and liver X receptor ligands with dissociated activity, which retain transrepression but have reduced transactivation potency, is also described. Conclusions: NF-κB inhibitors have yielded promising results in rodent models of inflammatory disease and cancer. Some of these are currently advancing into clinical trials.

Keywords::

• dissociated agonist
• glucocorticoid receptor
• IκB kinase
• ligand-mediated transrepression
• liver X receptor
• NF-κB
• PPAR

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