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Small Molecule NF-?B Pathway Inhibitors in Clinic.

ABSTRACT: Nuclear factor kappa B (NF-?B) signaling is implicated in all major human chronic diseases, with its role in transcription of hundreds of gene well established in the literature. This has propelled research into targeting the NF-?B pathways for modulating expression of those genes and the diseases mediated by them. In-spite of the critical, but often promiscuous role played by this pathway and the inhibition causing adverse drug reaction, currently many biologics, macromolecules, and small molecules that modulate this pathway are in the market or in clinical trials. Furthermore, many marketed drugs that were later found to also have NF-?B targeting activity were repurposed for new therapeutic interventions. Despite the rising importance of biologics in drug discovery, small molecules got around 76% of US-FDA (Food and Drug Administration-US) approval in the last decade. This encouraged us to review information regarding clinically relevant small molecule inhibitors of the NF-?B pathway from cell surface receptor stimulation to nuclear signaling. We have also highlighted the underexplored targets in this pathway that have potential to succeed in clinic.

SUBMITTER: Ramadass V

PROVIDER: S-EPMC7404026 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Small Molecule NF-κB Pathway Inhibitors in Clinic.

Ramadass Venkataramanan V Vaiyapuri Thamilselvan T Tergaonkar Vinay V

International journal of molecular sciences 20200721 14

Nuclear factor kappa B (NF-κB) signaling is implicated in all major human chronic diseases, with its role in transcription of hundreds of gene well established in the literature. This has propelled research into targeting the NF-κB pathways for modulating expression of those genes and the diseases mediated by them. In-spite of the critical, but often promiscuous role played by this pathway and the inhibition causing adverse drug reaction, currently many biologics, macromolecules, and small molec ...[more]

PMID: 32708302

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Project description:The activation of nuclear factor (NF)?B pathway and its transducing signaling cascade has been associated with the pathogenesis of many inflammatory diseases. The central role that I?B? and p65 phosphorylation play in regulating NF?B signalling in response to inflammatory stimuli made these proteins attractive targets for therapeutic strategies. Although several chemical classes of NF?B inhibitors have been identified, it is only for a few of those that a safety assessment based on a comprehensive understanding of their pharmacologic mechanism of action has been reported. Here, we describe the specific anti-inflammatory effect of bindarit, an indazolic derivative that has been proven to have anti-inflammatory activity in a variety of models of inflammatory diseases (including lupus nephritis, arthritis and pancreatitis). The therapeutic effects of bindarit have been associated with its ability to selectively interfere with monocyte recruitment and the "early inflammatory response," although its specific molecular mechanisms have remained ill-defined. For this purpose, we investigated the effect of bindarit on the LPS-induced production of inflammatory cytokines (MCP-1 and MCPs, IL-12?/p40, IL-6 and IL-8/KC) in both a mouse leukaemic monocyte-macrophage cell line and bone marrow derived macrophages (BMDM). Bindarit inhibits the LPS-induced MCP-1 and IL-12?/p40 expression without affecting other analyzed cytokines. The effect of bindarit is mediated by the downregulation of the classical NF?B pathway, involving a reduction of I?B? and p65 phosphorylation, a reduced activation of NF?B dimers and a subsequently reduced nuclear translocation and DNA binding. Bindarit showed a specific inhibitory effect on the p65 and p65/p50 induced MCP-1 promoter activation, with no effect on other tested activated promoters. We conclude that bindarit acts on a specific subpopulation of NF?B isoforms and selects its targets wihtin the whole NF?B inflammatory pathway. These findings pave the way for future applications of bindarit as modulator of the inflammatory response.

Dataset Information

Small Molecule NF-?B Pathway Inhibitors in Clinic.

Publications

Small Molecule NF-κB Pathway Inhibitors in Clinic.

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