Bindarit An anti-inflammatory small molecule that modulates the NF kappa B pathway

The activation of nuclear factor (NF)kappa B pathway and its transducing signaling cascade has been associated with the pathogenesis of many inflammatory diseases. The central role that IkB alpha and p65 phosphorylation play in regulating NFkB signalling in response to inflammatory stimuli made these proteins attractive targets for therapeutic strategies. Although several chemical classes of NFkB 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 beta/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-12b/p40 expression without affecting other analyzed cytokines. The effect of bindarit is mediated by the downregulation of the classical NFkB pathway, involving a reduction of IkBa and p65 phosphorylation, a reduced activation of NFkB 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 NFkB isoforms and selects its targets wihtin the whole NFkB inflammatory pathway. These findings pave the way for future applications of bindarit as modulator of the inflammatory response.