Novel small molecule inhibitors of tlr7 and tlr9: Mechanism of action and efficacy in vivo

Molecular Pharmacology

Volumn 85, Issue 3, 2014, Pages 429-440

  Lamphier, Marc ^a   Zheng, Wanjun ^a   Latz, Eicke ^a,b,c   Spyvee, Mark ^a   Hansen, Hans ^a   Rose, Jeffrey ^a   Genest, Melinda ^a   Yang, Hua ^a   Shaffer, Christina ^a   Zhao, Yan ^a   Shen, Yongchun ^a   Liu, Carrie ^a   Liu, Diana ^a   Mempel, Thorsten R ^a,d,e   Rowbottom, Christopher ^a   Chow, Jesse ^a   Twine, Natalie C ^a   Yu, Melvin ^a   Gusovsky, Fabian ^a   Ishizaka, Sally T ^a  

^a EISAI INC   (United States)

^b UNIVERSITY OF MASSACHUSETTS   (United States)

^c UNIVERSITY OF BONN   (Germany)

^d MASSACHUSETTS GENERAL HOSPITAL   (United States)

^e HARVARD MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMP-ACTIVATED PROTEIN KINASES; ANIMALS; CARRIER PROTEINS; CELL LINE; DOWN-REGULATION; DOXORUBICIN; MAP KINASE KINASE KINASE 5; MEMBRANE GLYCOPROTEINS; MICE; OXIDATIVE STRESS; P38 MITOGEN-ACTIVATED PROTEIN KINASES; PODOCYTES; REACTIVE OXYGEN SPECIES; SIGNAL TRANSDUCTION; SMALL MOLECULE LIBRARIES; THIOREDOXINS; TOLL-LIKE RECEPTOR 7; TOLL-LIKE RECEPTOR 9;

EID: 84894063872     PISSN: 0026895X     EISSN: 15210111     Source Type: Journal    
DOI: 10.1124/mol.113.089821     Document Type: Article

References (33)

1. Barbalat R, Ewald SE, Mouchess ML, and Barton GM (2011) Nucleic acid recognition by the innate immune system. Annu Rev Immunol 29:185-214.
2. Bamboat ZM, Balachandran VP, Ocuin LM, Obaid H, Plitas G, and DeMatteo RP (2010) Toll-like receptor 9 inhibition confers protection from liver ischemiareperfusion injury. Hepatology 51:621-632.
3. Barrat FJ, Meeker T, Chan JH, Guiducci C, and Coffman RL (2007) Treatment of lupus-prone mice with a dual inhibitor of TLR7 and TLR9 leads to reduction of autoantibody production and amelioration of disease symptoms. Eur J Immunol 37:3582-3586.
4. Barton GM, Kagan JC, and Medzhitov R (2006) Intracellular localization of Toll-like receptor 9 prevents recognition of self DNA but facilitates access to viral DNA. Nat Immunol 7:49-56.
5. Calcaterra C, Sfondrini L, Rossini A, Sommariva M, Rumio C, Ménard S, and Balsari A (2008) Critical role of TLR9 in acute graft-versus-host disease. J Immunol 181: 6132-6139.
6. Christensen SR, Kashgarian M, Alexopoulou L, Flavell RA, Akira S, and Shlomchik MJ (2005) Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus. J Exp Med 202:321-331.
7. Christensen SR, Shupe J, Nickerson K, Kashgarian M, Flavell RA, and Shlomchik MJ (2006) Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity 25:417-428.
8. Cohen SN and Yielding KL (1965) Spectrophotometric studies of the interaction of chloroquine with deoxyribonucleic acid. J Biol Chem 240:3123-3131.
9. de Duve C, de Barsy T, Poole B, Trouet A, Tulkens P, and Van Hoof F (1974) Commentary. Lysosomotropic agents. Biochem Pharmacol 23:2495-2531.
10. Franklin BS, Ishizaka ST, Lamphier M, Gusovsky F, Hansen H, Rose J, Zheng W, Ataíde MA, de Oliveira RB, and Golenbock DT et al. (2011) Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria. Proc Natl Acad Sci USA 108:3689-3694.
11. French JK, Hurst NP, O'Donnell ML, and Betts WH (1987) Uptake of chloroquine and hydroxychloroquine by human blood leucocytes in vitro: Relation to cellular concentrations during antirheumatic therapy. Ann Rheum Dis 46:42-45.
12. Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, Horiuchi T, Tomizawa H, Takeda K, and Akira S (2002) Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol 3:196-200.
13. Hoque R, Sohail M, Malik A, Sarwar S, Luo Y, Shah A, Barrat F, Flavell R, Gorelick F, and Husain S et al. (2011) TLR9 and the NLRP3 inflammasome link acinar cell death with inflammation in acute pancreatitis. Gastroenterology 141:358-369.
14. Itagaki K, Adibnia Y, Sun S, Zhao C, Sursal T, Chen Y, Junger W, and Hauser CJ (2011) Bacterial DNA induces pulmonary damage via TLR-9 through cross-talk with neutrophils. Shock 36:548-552.
15. Ishizaka S (2008) Development and in vivo assessment of TLR9 inhibitors; Toll 2008: Recent Advances in Pattern Recognition; 2008 Sept 24-27; Cascais, Portugal.
16. Jordan P, Brookes JG, Nikolic G, and Le Couteur DG (1999) Hydroxychloroquine overdose: Toxicokinetics and management. J Toxicol Clin Toxicol 37:861-864.
17. Kimball A, Krueger J, Sullivan T, and Arbeit R(2013) IMO-3100, an antagonist of TLR7 and TLR9, demonstrates clinical activity in psoriasis patients with 4 weeks of treatment in a phase 2a trial. Abstract 158, International Investigative Dermatology, 2013 May 8-11, 2013.
18. Klaschik S, Gursel I, and Klinman DM (2007) CpG-mediated changes in gene expression in murine spleen cells identified by microarray analysis. Mol Immunol 44: 1095-1104.
19. Kuznik A, Bencina M, Svajger U, Jeras M, Rozman B, and Jerala R (2011) Mechanism of endosomal TLR inhibition by antimalarial drugs and imidazoquinolines. J Immunol 186:4794-4804.
20. Latz E, Schoenemeyer A, Visintin A, Fitzgerald KA, Monks BG, Knetter CF, Lien E, Nilsen NJ, Espevik T, and Golenbock DT (2004) TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat Immunol 5:190-198.
21. Latz E, Verma A, Visintin A, Gong M, Sirois CM, Klein DC, Monks BG, McKnight CJ, Lamphier MS, and Duprex WP et al. (2007) Ligand-induced conformational changes allosterically activate Toll-like receptor 9. Nat Immunol 8:772-779.
22. Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Shlomchik MJ, and Marshak-Rothstein A (2002) Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416:603-607.
23. Macfarlane DE and Manzel L (1998) Antagonism of immunostimulatory CpGoligodeoxynucleotides by quinacrine, chloroquine, and structurally related compounds. J Immunol 160:1122-1131.
24. Manzel L, Strekowski L, Ismail FM, Smith JC, and Macfarlane DE (1999) Antagonism of immunostimulatory CpG-oligodeoxynucleotides by 4-aminoquinolines and other weak bases: Mechanistic studies. J Pharmacol Exp Ther 291:1337-1347.
25. Marshak-Rothstein A (2006) Toll-like receptors in systemic autoimmune disease. Nat Rev Immunol 6:823-835.
26. Means TK, Latz E, Hayashi F, Murali MR, Golenbock DT, and Luster AD (2005) Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. J Clin Invest 115:407-417.
27. Nickerson KM, Christensen SR, Shupe J, Kashgarian M, Kim D, Elkon K, and Shlomchik MJ (2010) TLR9 regulates TLR7-and MyD88-dependent autoantibody production and disease in a murine model of lupus. J Immunol 184:1840-1848.
28. Pawar RD, Ramanjaneyulu A, Kulkarni OP, Lech M, Segerer S, and Anders H-J (2007) Inhibition of Toll-like receptor-7 (TLR-7) or TLR-7 plus TLR-9 attenuates glomerulonephritis and lung injury in experimental lupus. J Am Soc Nephrol 18:1721-1731.
29. Sasai M and Yamamoto M (2013) Pathogen recognition receptors: Ligands and signaling pathways by Toll-like receptors. Int Rev Immunol 32:116-133.
30. Tett SE, Cutler DJ, Day RO, and Brown KF (1989) Bioavailability of hydroxychloroquine tablets in healthy volunteers. Br J Clin Pharmacol 27:771-779.
31. Vallin H, Perers A, Alm GV, and Rönnblom L (1999) Anti-double-stranded DNA antibodies and immunostimulatory plasmid DNA in combination mimic the endogenous IFN-a inducer in systemic lupus erythematosus. J Immunol 163: 6306-6313.
32. Wohnsland F and Faller B (2001) High-throughput permeability pH profile and highthroughput alkane/water log P with artificial membranes. J Med Chem 44: 923-930.
33. Wu X and Peng SL (2006) Toll-like receptor 9 signaling protects against murine lupus. Arthritis Rheum 54:336-342.