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

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Nuclear-Factor kappa B (NF-κB) is an inducible transcription factor of the Rel family, sequestered in the cytoplasm by the IkB family of proteins. NF-κB exists in several dimeric forms, but the p50 / p65 heterodimer is the predominant one. Activation of NF-κB by a range of physical, chemical, and biological stimuli leads to phosphorylation and proteasome dependent degradation of IkB, leading to the release of free NF-κB. This free NF-κB then binds to its target sites (kB 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-κB mediated transcription is presented. Next, comprehensive information on the current inhibitors which are targeted to interfere with the NF-κB pathway is provided. This latter section presents a critical review on different types of latest inhibitors targeting the complex NF-κB pathway at several stages. The inhibitors developed till date and still under investigation, include mainly those which interfere with the activation of NF-κB. Based on the complexity of NF-κB activation, and the current knowledge of the structural biology of NF-κB-DNA binding, finally it is proposed that a better approach to inhibit NF-κB 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-κB (p50 subunit), so as to generate more specific and selective leads of NF-κB-DNA binding.

Keywords: cancer; degradation; dna-binding; ikb; inflammatory diseases; kinases; oxidative stress; phosphorylation; viral diseases

Document Type: Review Article


Affiliations: REQUIMTE, Departamento de Quimica, Faculdade de Ciencias, Universidade do Porto, Rua do Campo Alegre 687, 4169-007 Porto, Portugal.

Publication date: February 1, 2005

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.

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