Selective inhibition of spleen tyrosine kinase (SYK) with a novel orally bioavailable small molecule inhibitor, RO9021, impinges on various innate and adaptive immune responses: Implications for SYK inhibitors in autoimmune disease therapy

Arthritis Research and Therapy

Volumn 15, Issue 5, 2013, Pages

  Liao, Cheng ^a,e   Hsu, Jonathan ^a,f   Kim, Yong ^a   Hu, Dong Qing ^a   Xu, Daigen ^a,e   Zhang, Jun ^a   Pashine, Achal ^a   Menke, John ^a   Whittard, Toni ^a   Romero, Natasha ^b   Truitt, Theresa ^b   Slade, Michelle ^b   Lukacs, Christine ^b   Hermann, Johannes ^c   Zhou, Mingyan ^d   Lucas, Matthew ^c,g   Narula, Satwant ^a   DeMartino, Julie ^a,e   Tan, Seng Lai ^a,e  

^a Inflammation Discovery Therapeutic Area   (United States)

^b Discovery Technology   (Finland)

^c Discovery Chemistry   (United States)

^d Drug Metabolism and Pharmacokinetics   (United States)

^e EMD Serono Research Institute   (United States)

^f ELI LILLY AND COMPANY   (United States)

^g CUBIST PHARMACEUTICALS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

6 [2 AMINO CYCLOHEXYLAMINO] 4 (5,6 DIMETHYL PYRIDIN 2 YLAMINO)PYRIDAZINE 3 CARBOXYLIC ACID AMIDE; B LYMPHOCYTE RECEPTOR; BREAKPOINT CLUSTER REGION PROTEIN; CD69 ANTIGEN; IMMUNOGLOBULIN G; IMMUNOGLOBULIN M; INTERFERON; JANUS KINASE; PROTEIN KINASE SYK; PROTEIN KINASE SYK INHIBITOR; RO 9021; STAT PROTEIN; TOFACITINIB; TOLL LIKE RECEPTOR 4; TOLL LIKE RECEPTOR 9; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG; 6 (2 AMINOCYCLOHEXYLAMINO) 4 (5,6 DIMETHYLPYRIDIN 2 YLAMINO)PYRIDAZINE 3 CARBOXYLIC ACID AMIDE; 6-(2-AMINOCYCLOHEXYLAMINO)-4-(5,6-DIMETHYLPYRIDIN-2-YLAMINO)PYRIDAZINE-3-CARBOXYLIC ACID AMIDE; AMINOPYRIDINE DERIVATIVE; PROTEIN KINASE INHIBITOR; PROTEIN TYROSINE KINASE; PYRIDAZINE DERIVATIVE; SIGNAL PEPTIDE;

ADAPTIVE IMMUNITY; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTHRITIS; ARTICLE; AUTOIMMUNE DISEASE; B LYMPHOCYTE; B LYMPHOCYTE ACTIVATION; B LYMPHOCYTE DIFFERENTIATION; BLOOD; BONE MARROW CELL; CONTROLLED STUDY; CYTOKINE PRODUCTION; DISEASE COURSE; DRUG BIOAVAILABILITY; DRUG SCREENING; DRUG SELECTIVITY; ENZYME ACTIVITY; ENZYME INHIBITION; ENZYME SPECIFICITY; HUMAN; HUMAN CELL; IN VITRO STUDY; INNATE IMMUNITY; INTERFERON PRODUCTION; MACROPHAGE; MAST CELL; MONOCYTE; MOUSE; NONHUMAN; OSTEOCLASTOGENESIS; PERIPHERAL BLOOD MONONUCLEAR CELL; PLASMACYTOID DENDRITIC CELL; SIGNAL TRANSDUCTION; ANIMAL; C57BL MOUSE; CELL CULTURE; CHEMICAL STRUCTURE; CHEMISTRY; CYTOLOGY; DBA MOUSE; DRUG ANTAGONISM; DRUG EFFECT; EXPERIMENTAL ARTHRITIS; FLOW CYTOMETRY; IMMUNOLOGY; JURKAT CELL LINE; METABOLISM; MOLECULAR LIBRARY; ORAL DRUG ADMINISTRATION; OSTEOCLAST; PROTEIN BINDING; PROTEIN TERTIARY STRUCTURE; TUMOR CELL LINE;

ADAPTIVE IMMUNITY; ADMINISTRATION, ORAL; AMINOPYRIDINES; ANIMALS; ARTHRITIS, EXPERIMENTAL; AUTOIMMUNE DISEASES; B-LYMPHOCYTES; CELL LINE, TUMOR; CELLS, CULTURED; FLOW CYTOMETRY; HUMANS; IMMUNITY, INNATE; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; JURKAT CELLS; MACROPHAGES; MICE; MICE, INBRED C57BL; MICE, INBRED DBA; MODELS, MOLECULAR; MOLECULAR STRUCTURE; OSTEOCLASTS; PROTEIN BINDING; PROTEIN KINASE INHIBITORS; PROTEIN STRUCTURE, TERTIARY; PROTEIN-TYROSINE KINASES; PYRIDAZINES; SIGNAL TRANSDUCTION; SMALL MOLECULE LIBRARIES;

EID: 84886741044     PISSN: 14786354     EISSN: 14786362     Source Type: Journal    
DOI: 10.1186/ar4329     Document Type: Article

References (43)

1. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med 2011, 365:2205-2219. 10.1056/NEJMra1004965, 22150039.
2. Tan S, Liao C, Lucas C, Stevenson C, DeMartino J. Targeting the SYK-BTK axis for the treatment of immunological and hematological disorders: recent progress and therapeutic perspectives. Pharmacol Ther 2013, 138(2):294-309. 10.1016/j.pharmthera.2013.02.001, 23396081.
3. Fabian MA, Biggs WH, Treiber DK, Atteridge CE, Azimioara MD, Benedetti MG, Carter TA, Ciceri P, Edeen PT, Floyd M, Ford JM, Galvin M, Gerlach JL, Grotzfeld RM, Herrgard S, Insko DE, Insko MA, Lai AG, Lélias JM, Mehta SA, Milanov ZV, Velasco AM, Wodicka LM, Patel HK, Zarrinkar PP, Lockhart DJ. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 2005, 23:329-336. 10.1038/nbt1068, 15711537.
4. Papp E, Tse JK, Ho H, Wang S, Shaw D, Lee S, Barnett J, Swinney DC, Bradshaw JM. Steady state kinetics of spleen tyrosine kinase investigated by a real time fluorescence assay. Biochemistry 2007, 46:15103-15114. 10.1021/bi701596u, 18052078.
5. Schmitz R, Baumann G, Gram H. Catalytic specificity of phosphotyrosine kinases Blk, Lyn, c-Src and Syk as assessed by phage display. J Mol Biol 1996, 260:664-677. 10.1006/jmbi.1996.0429, 8709147.
6. Baldock D, Graham B, Akhlaq M, Graff P, Jones CE, Menear K. Purification and characterization of human Syk produced using a baculovirus expression system. Protein Expr Purif 2000, 18:86-94. 10.1006/prep.1999.1171, 10648173.
7. Villasenor AG, Kondru R, Ho H, Wang S, Papp E, Shaw D, Barnett JW, Browner MF, Kuglstatter A. Structural insights for design of potent spleen tyrosine kinase inhibitors from crystallographic analysis of three inhibitor complexes. Chem Biol Drug Des 2009, 73:466-470. 10.1111/j.1747-0285.2009.00785.x, 19220318.
8. Atwell S, Adams JM, Badger J, Buchanan MD, Feil IK, Froning KJ, Gao X, Hendle J, Keegan K, Leon BC, Müller-Dieckmann HJ, Nienaber VL, Noland BW, Post K, Rajashankar KR, Ramos A, Russell M, Burley SK, Buchanan SG. A novel mode of Gleevec binding is revealed by the structure of spleen tyrosine kinase. J Biol Chem 2004, 279:55827-55832. 10.1074/jbc.M409792200, 15507431.
9. Xu D, Kim Y, Postelnek J, Vu MD, Hu DQ, Liao C, Bradshaw M, Hsu J, Zhang J, Pashine A, Srinivasan D, Woods J, Levin A, O'Mahony A, Owens TD, Lou Y, Hill RJ, Narula S, DeMartino J, Fine JS. RN486, a selective Bruton's tyrosine kinase inhibitor, abrogates immune hypersensitivity responses and arthritis in rodents. J Pharma Exper Ther 2012, 341:90-103.
10. Takami M, Kim N, Rho J, Choi Y. Stimulation by toll-like receptors inhibits osteoclast differentiation. J Immunol 2002, 169:1516-1523.
11. Takeshita S, Kaji K, Kudo A. Identification and characterization of the new osteoclast progenitor with macrophage phenotypes being able to differentiate into mature osteoclasts. J Bone Miner Res 2000, 15:1477-1488. 10.1359/jbmr.2000.15.8.1477, 10934646.
12. Kobayashi K, Takahashi N, Jimi E, Udagawa N, Takami M, Kotake S, Nakagawa N, Kinosaki M, Yamaguchi K, Shima N, Yasuda H, Morinaga T, Higashio K, Martin TJ, Suda T. Tumor necrosis factor alpha stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction. J Exp Med 2000, 191:275-286. 10.1084/jem.191.2.275, 2195746, 10637272.
13. Moon JB, Kim JH, Kim K, Youn BU, Ko A, Lee SY, Kim N. Akt induces osteoclast differentiation through regulating the GSK3beta/NFATc1 signaling cascade. J Immunol 2012, 188:163-169. 10.4049/jimmunol.1101254, 22131333.
14. Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP. A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol 2008, 26:127-132. 10.1038/nbt1358, 18183025.
15. Lucas MC, Goldstein DM, Hermann JC, Kuglstatter A, Liu W, Luk KC, Padilla F, Slade M, Villasenor AG, Wanner J, Xie W, Zhang X, Liao C. Rational design of highly selective spleen tyrosine kinase inhibitors. J Med Chem 2012, 55:10414-10423. 10.1021/jm301367c, 23151054.
16. Romas E, Gillespie MT, Martin TJ. Involvement of receptor activator of NFkappaB ligand and tumor necrosis factor-alpha in bone destruction in rheumatoid arthritis. Bone 2002, 30:340-346. 10.1016/S8756-3282(01)00682-2, 11856640.
17. Schett G. Osteoimmunology in rheumatic diseases. Arthritis Res Ther 2009, 11:210. 10.1186/ar2571, 2688223, 19232069.
18. Goldring SR. Pathogenesis of bone and cartilage destruction in rheumatoid arthritis. Rheumatology 2003, 42:ii11-ii16.
19. Zou W, Reeve JL, Liu Y, Teitelbaum SL, Ross FP. DAP12 couples c-Fms activation to the osteoclast cytoskeleton by recruitment of Syk. Mol Cell 2008, 31:422-431. 10.1016/j.molcel.2008.06.023, 2584874, 18691974.
20. Zou W, Kitaura H, Reeve J, Long F, Tybulewicz VL, Shattil SJ, Ginsberg MH, Ross FP, Teitelbaum SL. Syk, c-Src, the alphavbeta3 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption. J Cell Biol 2007, 176:877-888. 10.1083/jcb.200611083, 2064061, 17353363.
21. Mocsai A, Humphrey MB, Van Ziffle JA, Hu Y, Burghardt A, Spusta SC, Majumdar S, Lanier LL, Lowell CA, Nakamura MC. The immunomodulatory adapter proteins DAP12 and Fc receptor gamma-chain (FcRgamma) regulate development of functional osteoclasts through the Syk tyrosine kinase. Proc Natl Acad Sci U S A 2004, 101:6158-6163. 10.1073/pnas.0401602101, 395939, 15073337.
22. Koga T, Inui M, Inoue K, Kim S, Suematsu A, Kobayashi E, Iwata T, Ohnishi H, Matozaki T, Kodama T, Taniguchi T, Takayanagi H, Takai T. Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature 2004, 428:758-763. 10.1038/nature02444, 15085135.
23. Jakus Z, Simon E, Balazs B, Mocsai A. Genetic deficiency of Syk protects mice from autoantibody-induced arthritis. Arthritis Rheum 2010, 62:1899-1910. 2972644, 20201079.
24. Honda F, Kano H, Kanegane H, Nonoyama S, Kim ES, Lee SK, Takagi M, Mizutani S, Morio T. The kinase Btk negatively regulates the production of reactive oxygen species and stimulation-induced apoptosis in human neutrophils. Nat Immunol 2012, 13:369-378. 10.1038/ni.2234, 22366891.
25. Liu X, Zhan Z, Li D, Xu L, Ma F, Zhang P, Yao H, Cao X. Intracellular MHC class II molecules promote TLR-triggered innate immune responses by maintaining activation of the kinase Btk. Nat Immunol 2011, 12:416-424. 10.1038/ni.2015, 21441935.
26. Giordani L, Sanchez M, Libri I, Quaranta MG, Mattioli B, Viora M. IFN-alpha amplifies human naive B cell TLR-9-mediated activation and Ig production. J Leukocyte Biol 2009, 86:261-271. 10.1189/jlb.0908560, 19401392.
27. Kiefer K, Oropallo MA, Cancro MP, Marshak-Rothstein A. Role of type I interferons in the activation of autoreactive B cells. Immunol Cell Biol 2012, 90:498-504. 10.1038/icb.2012.10, 3701256, 22430248.
28. Zikherman J, Weiss A. Antigen receptor signaling in the rheumatic diseases. Arthritis Res Ther 2009, 11:202. 2688213, 19232064.
29. Berg EL. Phenotypic approaches defining toxicity mechanisms. Sanford Burnham Satellite Symposium 2013, Orlando, FL: Destination Drug Discovery at SLAS: Conference presentation at the 2013 Society for Laboratory Automation and Screening (SLAS).
30. Pathak S, Mohan C. Cellular and molecular pathogenesis of systemic lupus erythematosus: lessons from animal models. Arthritis Res Ther 2011, 13:241. 10.1186/ar3465, 3308079, 21989039.
31. Rahman A, Isenberg DA. Systemic lupus erythematosus. N Engl J Med 2008, 358:929-939. 10.1056/NEJMra071297, 18305268.
32. Bosch X. Systemic lupus erythematosus and the neutrophil. N Engl J Med 2011, 365:758-760. 10.1056/NEJMcibr1107085, 21864171.
33. Theofilopoulos AN. TLRs and IFNs: critical pieces of the autoimmunity puzzle. J Clin Invest 2012, 122:3464-3466. 10.1172/JCI63835, 3461918, 23154274.
34. Celhar T, Magalhaes R, Fairhurst AM. TLR7 and TLR9 in SLE: when sensing self goes wrong. Immunol Res 2012, 53:58-77. 10.1007/s12026-012-8270-1, 22434514.
35. Sanjuan MA, Rao N, Lai KT, Gu Y, Sun S, Fuchs A, Fung-Leung WP, Colonna M, Karlsson L. CpG-induced tyrosine phosphorylation occurs via a TLR9-independent mechanism and is required for cytokine secretion. J Cell Biol 2006, 172:1057-1068. 10.1083/jcb.200508058, 2063763, 16567503.
36. Sun S, Rao NL, Venable J, Thurmond R, Karlsson L. TLR7/9 antagonists as therapeutics for immune-mediated inflammatory disorders. Inflamm Allergy Drug Targets 2007, 6:223-235. 10.2174/187152807783334300, 18220957.
37. Lee YH, Bae SC, Kim JH, Song GG. Toll-like receptor polymorphisms and rheumatoid arthritis: a systematic review. Rheumatol Int 2013, [Epub ahead of print].
38. Takagi M. Toll-like receptor - a potent driving force behind rheumatoid arthritis. J Clin Exp Hematop 2011, 51:77-92. 10.3960/jslrt.51.77, 22104306.
39. Tamaki Y, Takakubo Y, Hirayama T, Konttinen YT, Goodman SB, Yamakawa M, Takagi M. Expression of Toll-like receptors and their signaling pathways in rheumatoid synovitis. J Rheumatol 2011, 38:810-820. 10.3899/jrheum.100732, 21324962.
40. Barrat FJ, Coffman RL. Development of TLR inhibitors for the treatment of autoimmune diseases. Immunol Rev 2008, 223:271-283. 10.1111/j.1600-065X.2008.00630.x, 18613842.
41. Santegoets KC, van Bon L, van den Berg WB, Wenink MH, Radstake TR. Toll-like receptors in rheumatic diseases: are we paying a high price for our defense against bugs?. FEBS Lett 2011, 585:3660-3666. 10.1016/j.febslet.2011.04.028, 21513712.
42. Pawar RD, Ramanjaneyulu A, Kulkarni OP, Lech M, Segerer S, Anders HJ. 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 2007, 18:1721-1731. 10.1681/ASN.2006101162, 17460144.
43. Barrat FJ, Meeker T, Chan JH, Guiducci C, Coffman RL. 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 2007, 37:3582-3586. 10.1002/eji.200737815, 18034431.