Members of the IKK {IκB [inhibitor of NF-κB (nuclear factor κB)] kinase} family play a central role in innate immunity by inducing NF-κB- and IRF [IFN (interferon) regulatory factor]-dependent gene transcription programmes required for the production of pro-inflammatory cytokines and IFNs[3]. MRT67307 is a dual inhibitor of the IKKε and TBK-1 (TANK-binding Kinase 1) with IC50s of 19 and 160 nM in vitro[3]. In IKKα−/−MEFs (mouse embryonic fibroblasts), MRT67307 enhanced the IL-1-stimulated phosphorylation of RelA at Ser468. Similarly, in wild type MEFs, MRT67307 enhanced the IL-1-stimulated phosphorylation of p105 at Ser933 and RelA at both Ser468 and Ser536. MRT67307 also enhanced IL-1-stimulated activation of NF-κB -dependent gene transcription in wild type MEFs. Treatment of macrophages with MRT67307 enhanced the poly(I:C)-stimulated phosphorylation of TBK1 at Ser172 and enhanced the catalytic activity of IKK and TBK1. Additionally, Treatment of macrophages with MRT67307 led to an increase in the poly(I:C) and LPS-stimulated phosphorylation of p105 and RelA and enhanced NF-κB transcriptional activity[3].
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