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Mol Pharmacol. 2014 Mar;85(3):429-40. doi: 10.1124/mol.113.089821. Epub 2013 Dec 16.

Novel small molecule inhibitors of TLR7 and TLR9: mechanism of action and efficacy in vivo.

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  • 1Eisai, Inc., Andover, Massachusetts (M.L., W.Z., M.S., H.H., J.R., M.G., H.Y., C.S., Y.Z., Y.S., C.L., D.L., C.R., J.C., N.C.T., M.Y., F.G., S.T.I.); Department of Infectious Diseases and Immunology, University of Massachusetts, Worcester, Massachusetts (E.L.); Institute of Innate Immunity, University of Bonn, Germany (E.L.); Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown, Massachusetts (T.R.M.); and Center for Systems Biology, Harvard Medical School, Charlestown, Massachusetts (T.R.M.).


The discovery that circulating nucleic acid-containing complexes in the serum of autoimmune lupus patients can stimulate B cells and plasmacytoid dendritic cells via Toll-like receptors 7 and 9 suggested that agents that block these receptors might be useful therapeutics. We identified two compounds, AT791 {3-[4-(6-(3-(dimethylamino)propoxy)benzo[d]oxazol-2-yl)phenoxy]-N,N-dimethylpropan-1-amine} and E6446 {6-[3-(pyrrolidin-1-yl)propoxy)-2-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl]benzo[d]oxazole}, that inhibit Toll-like receptor (TLR)7 and 9 signaling in a variety of human and mouse cell types and inhibit DNA-TLR9 interaction in vitro. When administered to mice, these compounds suppress responses to challenge doses of cytidine-phosphate-guanidine (CpG)-containing DNA, which stimulates TLR9. When given chronically in spontaneous mouse lupus models, E6446 slowed development of circulating antinuclear antibodies and had a modest effect on anti-double-stranded DNA titers but showed no observable impact on proteinuria or mortality. We discovered that the ability of AT791 and E6446 to inhibit TLR7 and 9 signaling depends on two properties: weak interaction with nucleic acids and high accumulation in the intracellular acidic compartments where TLR7 and 9 reside. Binding of the compounds to DNA prevents DNA-TLR9 interaction in vitro and modulates signaling in vivo. Our data also confirm an earlier report that this same mechanism may explain inhibition of TLR7 and 9 signaling by hydroxychloroquine (Plaquenil; Sanofi-Aventis, Bridgewater, NJ), a drug commonly prescribed to treat lupus. Thus, very different structural classes of molecules can inhibit endosomal TLRs by essentially identical mechanisms of action, suggesting a general mechanism for targeting this group of TLRs.

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