TY - JOUR T1 - Novel Small Molecule Inhibitors of TLR7 and TLR9: Mechanism of Action and Efficacy In Vivo JF - Molecular Pharmacology JO - Mol Pharmacol SP - 429 LP - 440 DO - 10.1124/mol.113.089821 VL - 85 IS - 3 AU - Marc Lamphier AU - Wanjun Zheng AU - Eicke Latz AU - Mark Spyvee AU - Hans Hansen AU - Jeffrey Rose AU - Melinda Genest AU - Hua Yang AU - Christina Shaffer AU - Yan Zhao AU - Yongchun Shen AU - Carrie Liu AU - Diana Liu AU - Thorsten R. Mempel AU - Christopher Rowbottom AU - Jesse Chow AU - Natalie C. Twine AU - Melvin Yu AU - Fabian Gusovsky AU - Sally T. Ishizaka Y1 - 2014/03/01 UR - http://molpharm.aspetjournals.org/content/85/3/429.abstract N2 - 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. ER -