886
Views
10
CrossRef citations to date
0
Altmetric
Review

Investigational spleen tyrosine kinase (SYK) inhibitors for the treatment of autoimmune diseases

, & ORCID Icon
Pages 291-303 | Received 26 Aug 2021, Accepted 06 Feb 2022, Published online: 18 Feb 2022

References

  • Wang L, Wang F-S, Gershwin ME. Human autoimmune diseases: a comprehensive update. J Intern Med. 2015;278(4):369–395.
  • Scofield RH. Autoantibodies as predictors of disease. Lancet. 2004;363:1544–1546.
  • Colucci F, Guy-Grand D, Wilson A, et al. A new look at Syk in alpha beta and gamma delta T cell development using chimeric mice with a low competitive hematopoietic environment. J Immunol. 2000;164:5140–5145.
  • Mócsai A, Abram CL, Jakus Z, et al. Integrin signaling in neutrophils and macrophages uses adaptors containing immunoreceptor tyrosine-based activation motifs. Nat Immunol. 2006;7:1326–1333.
  • Liao C, Hsu J, Kim Y, et al. 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 Res Ther. 2013;15:R146.
  • Geahlen RL. Getting Syk: spleen tyrosine kinase as a therapeutic target. Trends Pharmacol Sci. 2014;35:414–422.
  • Mócsai A, Ruland J, Tybulewicz VL. The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat Rev Immunol. 2010;10:387–402.
  • Rolli V, Gallwitz M, Wossning T, et al. Amplification of B cell antigen receptor signaling by a Syk/ITAM positive feedback loop. Mol Cell. 2002;10:1057–1069.
  • Vilariño N, W MD Jr. Actin cytoskeleton-dependent down-regulation of early IgE-mediated signaling in human basophils. J Leukoc Biol. 2004;75:928–937.
  • Robak T, Robak E. Tyrosine kinase inhibitors as potential drugs for B-cell lymphoid malignancies and autoimmune disorders. Expert Opin Investig Drugs. 2012;21:921–947.
  • Zarrin AA, Bao K, Lupardus P, et al. Kinase inhibition in autoimmunity and inflammation. Nat Rev Drug Discov. 2021;20(1):39–63.
  • Braselmann S, Taylor V, Zhao H, et al. R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation. J Pharmacol Exp Ther. 2006;319:998–1008.
  • Wang W, Ren S, Lu Y, et al. Inhibition of Syk promotes chemical reprogramming of fibroblasts via metabolic rewiring and H2S production. EMBO J. 2021;40:e106771.
  • Sweeny DJ, Li W, Grossbard E, et al. Contribution of gut bacteria to the metabolism of the spleen tyrosine kinase (Syk) inhibitor R406 in cynomolgus monkey. Xenobiotica. 2010;40:415–423.
  • Yiu WH, Chan KW, Chan LYY, et al. Spleen tyrosine kinase inhibition ameliorates tubular inflammation in IgA nephropathy. Front Physiol. 2021;12:650888.
  • R PP, Chang B, Schoettler N, et al. Inflammation and bone erosion are suppressed in models of rheumatoid arthritis following treatment with a novel Syk inhibitor. Clin Immunol. 2007;124:244–257.
  • E WM, Kavanaugh A, Burgos-Vargas R, et al. Treatment of rheumatoid arthritis with a Syk kinase inhibitor: a twelve-week, randomized, placebo-controlled trial. Arthritis Rheum. 2008;58:3309–3318.
  • C GM, van der Heijde D M, C KE, et al. A phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study of 2 dosing regimens of fostamatinib in patients with rheumatoid arthritis with an inadequate response to a tumor necrosis factor-α antagonist. J Rheumatol. 2014;41:2120–2128.
  • S AK, Nadeem A, F AS, et al. Inhibition of spleen tyrosine kinase attenuates psoriasis-like inflammation in mice through blockade of dendritic cell-Th17 inflammation axis. Biomed Pharmacother. 2019;111:347–358.
  • Hewins P, Williams JM, Wakelam MJ, et al. Activation of Syk in neutrophils by antineutrophil cytoplasm antibodies occurs via Fcgamma receptors and CD18. J Am Soc Nephrol. 2004;15:796–808.
  • P MS, Prendecki M, Tanna A, et al. Spleen tyrosine kinase inhibition is an effective treatment for established vasculitis in a pre-clinical model. Kidney Int. 2020;97:1196–1207.
  • Chen L, Monti S, Juszczynski P, et al. SYK-dependent tonic B-cell receptor signaling is a rational treatment target in diffuse large B-cell lymphoma. Blood. 2008;111:2230–2237.
  • Kunwar S, Devkota AR, Ghimire DK. Fostamatinib, an oral spleen tyrosine kinase inhibitor, in the treatment of rheumatoid arthritis: a meta-analysis of randomized controlled trials. Rheumatol Int. 2016;36:1077–1087.
  • Scott DL. Role of spleen tyrosine kinase inhibitors in the management of rheumatoid arthritis. Drugs. 2011;71:1121–1132.
  • Riccaboni M, Bianchi I, Petrillo P. Spleen tyrosine kinases: biology, therapeutic targets and drugs. Drug Discov Today. 2010;15:517–530.
  • Can G, Ayvaz S, Can H, et al. The Syk inhibitor fostamatinib decreases the severity of colonic mucosal damage in a rodent model of colitis. J Crohns Colitis. 2015;9:907–917.
  • C GM, Kavanaugh A, E WM, et al. An oral Syk kinase inhibitor in the treatment of rheumatoid arthritis: a three-month randomized, placebo-controlled, phase II study in patients with active rheumatoid arthritis that did not respond to biologic agents. Arthritis Rheum. 2011;63:337–345.
  • Weinblatt ME, Kavanaugh A, Genovese MC, et al. An oral spleen tyrosine kinase (Syk) inhibitor for rheumatoid arthritis. N Engl J Med. 2010;363:1303–1312.
  • Tanaka Y, Millson D, Iwata S, et al. Safety and efficacy of fostamatinib in rheumatoid arthritis patients with an inadequate response to methotrexate in phase II OSKIRA-Asia-1 and OSKIRA-Asia-1X study. Rheumatology (Oxford). 2021;60:2884–2895.
  • Nijjar JS, Tindell A, McInnes IB, et al. Inhibition of spleen tyrosine kinase in the treatment of rheumatoid arthritis. Rheumatology (Oxford). 2013;52:1556–1562.
  • Salgado E, Maneiro JR, Carmona L, et al. Safety profile of protein kinase inhibitors in rheumatoid arthritis: systematic review and meta-analysis. Ann Rheum Dis. 2014;73:871–882.
  • E WM, C GM, Ho M, et al. Effects of fostamatinib, an oral spleen tyrosine kinase inhibitor, in rheumatoid arthritis patients with an inadequate response to methotrexate: results from a phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheumatol. 2014;66:3255–3264.
  • Maringwa J, Kågedal M, W HU, et al. Pharmacokinetic-pharmacodynamic modeling of fostamatinib efficacy on ACR20 to support dose selection in patients with rheumatoid arthritis (RA). J Clin Pharmacol. 2015;55:328–335.
  • C TP, C GM, Greenwood M, et al. OSKIRA-4: a phase IIb randomised, placebo-controlled study of the efficacy and safety of fostamatinib monotherapy. Ann Rheum Dis. 2015;74:2123–2129.
  • Kang Y, Jiang X, Qin D, et al. Efficacy and safety of multiple dosages of fostamatinib in adult patients with rheumatoid arthritis: a systematic review and meta-analysis. Front Pharmacol. 2019;10:897.
  • Markham A. Fostamatinib: first global approval. Drugs. 2018;78:959–963.
  • Newland A, Lee EJ, McDonald V, et al. Fostamatinib for persistent/chronic adult immune thrombocytopenia. Immunotherapy. 2018;10:9–25.
  • Bussel J, M AD, Grossbard E, et al. Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: results of two phase 3, randomized, placebo-controlled trials. Am J Hematol. 2018;93:921–930.
  • Cooper N, Altomare I, R TM, et al. Assessment of thrombotic risk during long-term treatment of immune thrombocytopenia with fostamatinib. Ther Adv Hematol. 2021;12:20406207211010875.
  • Suljagic M, G LP, Bennardo S, et al. The Syk inhibitor fostamatinib disodium (R788) inhibits tumor growth in the Eμ- TCL1 transgenic mouse model of CLL by blocking antigen-dependent B-cell receptor signaling. Blood. 2010;116:4894–4905.
  • J KM, P MJ, P MS, et al. Spleen tyrosine kinase is important in the production of proinflammatory cytokines and cell proliferation in human mesangial cells following stimulation with IgA1 isolated from IgA nephropathy patients. J Immunol. 2012;189:3751–3758.
  • Almaani S, Meara A, Rovin BH. Update on Lupus Nephritis. Clin J Am Soc Nephrol. 2017;12:825–835.
  • Deng GM, Liu L, Bahjat FR, et al. Suppression of skin and kidney disease by inhibition of spleen tyrosine kinase in lupus-prone mice. Arthritis Rheum. 2010;62:2086–2092.
  • R BF, R PP, Reitsma A, et al. An orally bioavailable spleen tyrosine kinase inhibitor delays disease progression and prolongs survival in murine lupus. Arthritis Rheum. 2008;58:1433–1444.
  • E DR, N NV, Lenz G, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature. 2010;463:88–92.
  • E SS, Coffey G, B FL, et al. The selective SYK inhibitor P505-15 (PRT062607) inhibits B cell signaling and function in vitro and in vivo and augments the activity of fludarabine in chronic lymphocytic leukemia. J Pharmacol Exp Ther. 2013;344:378–387.
  • Coffey G, Rani A, Betz A, et al. PRT062607 achieves complete inhibition of the spleen tyrosine kinase at tolerated exposures following oral dosing in healthy volunteers. J Clin Pharmacol. 2017;57:194–210.
  • Hoellenriegel J, P CG, Sinha U, et al. Selective, novel spleen tyrosine kinase (Syk) inhibitors suppress chronic lymphocytic leukemia B-cell activation and migration. Leukemia. 2012;26:1576–1583.
  • Coffey G, DeGuzman F, Inagaki M, et al. Specific inhibition of spleen tyrosine kinase suppresses leukocyte immune function and inflammation in animal models of rheumatoid arthritis. J Pharmacol Exp Ther. 2012;340:350–359.
  • Zhang Z, Cao C, Sun S, et al. Selective spleen tyrosine kinase inhibition delays autoimmune arthritis in mice. Mol Med Rep. 2015;12:2902–2906.
  • Llop-Guevara A, Porras M, Cendón C, et al. Simultaneous inhibition of JAK and SYK kinases ameliorates chronic and destructive arthritis in mice. Arthritis Res Ther. 2015;17:356.
  • Coffey G, Betz A, Graf J, et al. Methotrexate and a spleen tyrosine kinase inhibitor cooperate to inhibit responses to peripheral blood B cells in rheumatoid arthritis. Pharmacol Res Perspect. 2013;1:e00016.
  • S CK, E KJ, Lee T, et al. Discovery of GS-9973, a selective and orally efficacious inhibitor of spleen tyrosine kinase. J Med Chem. 2014;57:3856–3873.
  • Sharman J, Hawkins M, Kolibaba K, et al. An open-label phase 2 trial of entospletinib (GS-9973), a selective spleen tyrosine kinase inhibitor, in chronic lymphocytic leukemia. Blood. 2015;125:2336–2343.
  • Ramanathan S, Paolo J A D, Jin F, et al. Pharmacokinetics, pharmacodynamics, and safety of entospletinib, a novel pSYK inhibitor, following single and multiple oral dosing in healthy volunteers. Clin Drug Investig. 2017;37:195–205.
  • C PJ, Jia W, Paolo J A D, et al. SYK inhibitor entospletinib prevents ocular and skin GVHD in mice. JCI Insight. 2018;3:e122430.
  • V DA, Herbaux C, S WH, et al. Phase ib study of tirabrutinib in combination with idelalisib or entospletinib in previously treated chronic lymphocytic leukemia. Clin Cancer Res. 2020;26:2810–2818.
  • Morschhauser F, S DMJ, S WH, et al. Phase 1b study of tirabrutinib in combination with idelalisib or entospletinib in previously treated B-cell lymphoma. Leukemia. 2021;35:2108–2113.
  • S KA, Best S, Thurlow B, et al. Entospletinib and obinutuzumab in patients with relapsed/refractory chronic lymphocytic leukemia and B-cell malignancies. Haematologica. 2021;106:2022–2025.
  • Blomgren P, Chandrasekhar J, Paolo J A D, et al. Discovery of lanraplenib (GS-9876): a once-daily spleen tyrosine kinase inhibitor for autoimmune diseases. ACS Med Chem Lett. 2020;11:506–513.
  • Baker M, Chaichian Y, Genovese M, et al. Phase II, randomised, double-blind, multicentre study evaluating the safety and efficacy of filgotinib and lanraplenib in patients with lupus membranous nephropathy. RMD Open. 2020;6(3):e001490.
  • Kerschbaumer A, Sepriano A, S SJ, et al. Efficacy of pharmacological treatment in rheumatoid arthritis: a systematic literature research informing the 2019 update of the EULAR recommendations for management of rheumatoid arthritis. Ann Rheum Dis. 2020;79:744–759.
  • P WV, Fleischmann R, and Robern M, et al. Filgotinib or Lanraplenib in Moderate to Severe Cutaneous Lupus Erythematosus: a Phase 2, Randomised, Double-Blind, Placebo-Controlled Study. Rheumatology (Oxford). p. 1-11; 2021 .
  • W PC, Shang C, Han P, et al. Characterization of the mechanism of action of lanraplenib, a novel spleen tyrosine kinase inhibitor, in models of lupus nephritis. BMC Rheumatol. 2021;5:15.
  • S CA, Rousseau E, Wang K, et al. Effects of GS-9876, a novel spleen tyrosine kinase inhibitor, on platelet function and systemic hemostasis. Thromb Res. 2018;170:109–118.
  • Coffey G, Betz A, DeGuzman F, et al. The novel kinase inhibitor PRT062070 (Cerdulatinib) demonstrates efficacy in models of autoimmunity and B-cell cancer. J Pharmacol Exp Ther. 2014;351:538–548.
  • D BM, Koehrer S, C DR, et al. The dual Syk/jak inhibitor cerdulatinib antagonizes b-cell receptor and microenvironmental signaling in chronic lymphocytic leukemia. Clin Cancer Res. 2017;23:2313–2324.
  • Ishikawa C, Senba M, Mori N. Anti-adult T‑cell leukemia/lymphoma activity of cerdulatinib, a dual SYK/JAK kinase inhibitor. Int J Oncol. 2018;53:1681–1690.
  • P CG, Feng J, Betz A, et al. Cerdulatinib pharmacodynamics and relationships to tumor response following oral dosing in patients with relapsed/refractory b-cell malignancies. Clin Cancer Res. 2019;25:1174–1184.
  • A HP, W FI, Wagner-Johnston N, et al. Efficacy and safety of the dual SYK/JAK inhibitor cerdulatinib in patients with relapsed or refractory B-cell malignancies: results of a phase I study. Am J Hematol. 2019;94:E90–e93.
  • Tavakoli Shirazi P, Eadie LN, Page EC, et al. Constitutive JAK/STAT signaling is the primary mechanism of resistance to JAKi in TYK2-rearranged acute lymphoblastic leukemia. Cancer Lett. 2021;512:28–37.
  • C PS, B PA, McHale K, et al. A phase 1b, randomized, single-center trial of topical cerdulatinib (DMVT-502) in patients with mild-to-moderate atopic dermatitis. J Invest Dermatol. 2021;141:1847–1851.
  • Norman P. A novel Syk kinase inhibitor suitable for inhalation: r-343(?)–WO-2009031011. Expert Opin Ther Pat. 2009;19:1469–1472.
  • Denyer J, Patel V. Syk kinase inhibitors in allergic diseases. Drug News Perspect. 2009;22:146–150.
  • Niimi T, Orita M, Okazawa-Igarashi M, et al. Design and synthesis of non-peptidic inhibitors for the Syk C-terminal SH2 domain based on structure-based in-silico screening. J Med Chem. 2001;44:4737–4740.
  • B RA, Herlaar E, Braselmann S, et al. Identification of the Syk kinase inhibitor R112 by a human mast cell screen. J Allergy Clin Immunol. 2006;118:749–755.
  • Guyer BJ, Shimamoto SR, Bradhurst AL, et al. Mast cell inhibitor R112 is well tolerated and affects prostaglandin D2 but not other mediators, symptoms, or nasal volumes in a nasal challenge model of allergic rhinitis. Allergy Asthma Proc. 2006;27:208–213.
  • Meltzer EO, Berkowitz RB, Grossbard EB. An intranasal Syk-kinase inhibitor (R112) improves the symptoms of seasonal allergic rhinitis in a park environment. J Allergy Clin Immunol. 2005;115:791–796.
  • Jang JW, Park S, Moon EY. Spleen tyrosine kinase regulates crosstalk of hypoxia-inducible factor-1α and nuclear factor (erythroid-derived2)-like 2 for B cell survival. Int Immunopharmacol. 2021;95:107509.
  • Yamamoto N, Takeshita K, Shichijo M, et al. The orally available spleen tyrosine kinase inhibitor 2-[7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino]nicotinamide dihydrochloride (BAY 61-3606) blocks antigen-induced airway inflammation in rodents. J Pharmacol Exp Ther. 2003;306:1174–1181.
  • Perova T, Grandal I, M NL, et al. Therapeutic potential of spleen tyrosine kinase inhibition for treating high-risk precursor B cell acute lymphoblastic leukemia. Sci Transl Med. 2014;6:236ra62.
  • Tabeling C, Herbert J, C HA, et al. Spleen tyrosine kinase inhibition blocks airway constriction and protects from Th2-induced airway inflammation and remodeling. Allergy. 2017;72:1061–1072.
  • Du J, Wang Y, Chen D, et al. BAY61-3606 potentiates the anti-tumor effects of TRAIL against colon cancer through up-regulating DR4 and down-regulating NF-κB. Cancer Lett. 2016;383:145–153.
  • Ho CM, Donovan-Banfield IZ, Tan L, et al. Inhibition of IKKα by BAY61-3606 Reveals IKKα-Dependent Histone H3 Phosphorylation in Human Cytomegalovirus Infected Cells. PLoS One. 2016;11:e0150339.
  • Unsal D, Kacan M, Temiz-Resitoglu M, et al. The role of Syk/IĸB-α/NF-ĸB pathway activation in the reversal effect of BAY 61-3606, a selective Syk inhibitor, on hypotension and inflammation in a rat model of zymosan-induced non-septic shock. Clin Exp Pharmacol Physiol. 2018;45:155–165.
  • Wen HC, Huo YN, Chou CM, et al. PMA inhibits endothelial cell migration through activating the PKC-δ/Syk/NF-κB-mediated up-regulation of Thy-1. Sci Rep. 2018;8:16247.
  • Sahan-Firat S, Temiz-Resitoglu M, S GD, et al. NF-κB activation mediates LPS-or zymosan-induced hypotension and inflammation reversed by BAY61-3606, a selective Syk inhibitor, in rat models of septic and non-septic shock. Clin Exp Pharmacol Physiol. 2019;46:173–182.
  • Iwata S, Yamaoka K, Niiro H, et al. Increased Syk phosphorylation leads to overexpression of TRAF6 in peripheral B cells of patients with systemic lupus erythematosus. Lupus. 2015;24:695–704.
  • Liddle J, L AF, D BM, et al. Discovery of GSK143, a highly potent, selective and orally efficacious spleen tyrosine kinase inhibitor. Bioorg Med Chem Lett. 2011;21:6188–6194.
  • van Bree S H, J G-P-P, van de Bovenkamp F S, et al. Inhibition of spleen tyrosine kinase as treatment of postoperative ileus. Gut. 2013;62:1581–1590.
  • Salehi S, Wang X, Juvet S, et al. Syk Regulates Neutrophilic Airway Hyper-Responsiveness in a Chronic Mouse Model of Allergic Airways Inflammation. PLoS One. 2017;12:e0163614.
  • S CJ, J HH, W KS, et al. Highly potent and selective pyrazolylpyrimidines as Syk kinase inhibitors. Bioorg Med Chem Lett. 2015;25:4441–4446.
  • J LS, S CJ, M BS, et al. Crystal Structures of Spleen Tyrosine Kinase in Complex with Two Novel 4-Aminopyrido[4,3-d] Pyrimidine Derivative Inhibitors. Mol Cells. 2018;41:545–552.
  • Moriya K, Rivera J, Odom S, et al. ER-27319, an acridone-related compound, inhibits release of antigen-induced allergic mediators from mast cells by selective inhibition of fcepsilon receptor I-mediated activation of Syk. Proc Natl Acad Sci U S A. 1997;94:12539–12544.
  • Lusková P, Dráber P. Modulation of the Fce Receptor I Signaling by Tyrosine Kinase Inhibitors: search for Therapeutic Targets of Inflammatory and Allergy Diseases. Curr Pharm Des. 2004;10(15):107509–107537.
  • G VA, Kondru R, Ho H, et al. 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.
  • Fabian MA, Biggs WH, Treiber DK, et al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 2005;23:329–336.
  • Liu D, Mamorska-Dyga A. Syk inhibitors in clinical development for hematological malignancies. J Hematol Oncol. 2017;10:145.
  • Wang L, Aschenbrenner D, Zeng Z, et al. Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice. Nat Genet. 2021;53:500–510.
  • Leseux L, M HS, Al Saati T, et al. Syk-dependent mTOR activation in follicular lymphoma cells. Blood. 2006;108:4156–4162.
  • Banik K, M RA, Harsha C, et al. Piceatannol: a natural stilbene for the prevention and treatment of cancer. Pharmacol Res. 2020;153:104635.
  • Joshi S, X LK, Zulcic M, et al. Macrophage Syk-PI3Kγ Inhibits Antitumor Immunity: SRX3207, a Novel Dual Syk-PI3K Inhibitory Chemotype Relieves Tumor Immunosuppression. Mol Cancer Ther. 2020;19:755–764.
  • Wang C, Wang X, Li Y, et al. Design and optimization of orally spleen tyrosine kinase (SYK) inhibitors for treatment of solid tumor. Bioorg Chem. 2020;95:103547.
  • Khoo JK, Barnes H, Key S, et al. Pulmonary adverse events of small molecule JAK inhibitors in autoimmune disease: systematic review and meta-analysis. Rheumatology (Oxford). 2020;59:2217–2225.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.