Protein kinase inhibitors in the treatment of inflammatory and autoimmune diseases

Protein kinases mediate protein phosphorylation, which is a fundamental component of cell signalling, with crucial roles in most signal transduction cascades: from controlling cell growth and proliferation to the initiation and regulation of immunological responses. Aberrant kinase activity is implicated in an increasing number of diseases, with more than 400 human diseases now linked either directly or indirectly to protein kinases. Protein kinases are therefore regarded as highly important drug targets, and are the subject of intensive research activity. The success of small molecule kinase inhibitors in the treatment of cancer, coupled with a greater understanding of inflammatory signalling cascades, has led to kinase inhibitors taking centre stage in the pursuit for new anti‐inflammatory agents for the treatment of immune‐mediated diseases. Herein we discuss the main classes of kinase inhibitors; namely Janus kinase (JAK), mitogen‐activated protein kinase (MAPK) and spleen tyrosine kinase (Syk) inhibitors. We provide a mechanistic insight into how these inhibitors interfere with kinase signalling pathways and discuss the clinical successes and failures in the implementation of kinase‐directed therapeutics in the context of inflammatory and autoimmune disorders.

[1]  E. P. Kennedy,et al.  The enzymatic phosphorylation of proteins. , 1954, The Journal of biological chemistry.

[2]  J. Kremer,et al.  Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. , 2012, The New England journal of medicine.

[3]  Khusru Asadullah,et al.  Novel immunotherapies for psoriasis. , 2002, Trends in immunology.

[4]  Matthew R. Lee,et al.  MAP Kinase p38Inhibitors: Clinical Results and an Intimate Look at Their Interactions with p38α Protein , 2005 .

[5]  Teiji Wada,et al.  Mitogen-activated protein kinases in apoptosis regulation , 2004, Oncogene.

[6]  M. Mack,et al.  Interleukin-4 therapy of psoriasis induces Th2 responses and improves human autoimmune disease , 2003, Nature Medicine.

[7]  T. Yamamoto,et al.  Syk activation by the Src-family tyrosine kinase in the B cell receptor signaling , 1994, The Journal of experimental medicine.

[8]  S. Zahler,et al.  A role for Syk‐kinase in the control of the binding cycle of the β2 integrins (CD11/CD18) in human polymorphonuclear neutrophils , 2003, Journal of leukocyte biology.

[9]  T. Hunter,et al.  Evolution of protein kinase signaling from yeast to man. , 2002, Trends in biochemical sciences.

[10]  O. Silvennoinen,et al.  The Janus kinases (Jaks) , 2004, Genome Biology.

[11]  T. Hunter,et al.  The Protein Kinase Complement of the Human Genome , 2002, Science.

[12]  D. Payan,et al.  R406, an Orally Available Spleen Tyrosine Kinase Inhibitor Blocks Fc Receptor Signaling and Reduces Immune Complex-Mediated Inflammation , 2006, Journal of Pharmacology and Experimental Therapeutics.

[13]  P. Cohen Protein kinases — the major drug targets of the twenty-first century? , 2002, Nature reviews. Drug discovery.

[14]  Feifei Zhao,et al.  Inflammation and bone erosion are suppressed in models of rheumatoid arthritis following treatment with a novel Syk inhibitor. , 2007, Clinical immunology.

[15]  J. O’Shea,et al.  Jakinibs: a new class of kinase inhibitors in cancer and autoimmune disease. , 2012, Current opinion in pharmacology.

[16]  S. Kassis,et al.  Pharmacological effects of SB 220025, a selective inhibitor of P38 mitogen-activated protein kinase, in angiogenesis and chronic inflammatory disease models. , 1998, The Journal of pharmacology and experimental therapeutics.

[17]  Chen Dong,et al.  MAP kinases in the immune response. , 2002, Annual review of immunology.

[18]  P. Cohen,et al.  The origins of protein phosphorylation , 2002, Nature Cell Biology.

[19]  J. Johnston,et al.  Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID) , 1995, Nature.

[20]  N. Damjanov,et al.  Efficacy, pharmacodynamics, and safety of VX-702, a novel p38 MAPK inhibitor, in rheumatoid arthritis: results of two randomized, double-blind, placebo-controlled clinical studies. , 2009, Arthritis and rheumatism.

[21]  P. Malfertheiner,et al.  Inhibition of p38 MAP kinase‐and RICK/NF‐κB‐signaling suppresses inflammatory bowel disease , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[22]  John J. O’Shea,et al.  Kinase inhibitors in the treatment of immune-mediated disease , 2012, F1000 medicine reports.

[23]  J. Ferrell,et al.  Mechanisms of specificity in protein phosphorylation , 2007, Nature Reviews Molecular Cell Biology.

[24]  Georg Schett,et al.  Cytokines in the pathogenesis of rheumatoid arthritis , 2007, Nature Reviews Immunology.

[25]  P. Norman A novel Syk kinase inhibitor suitable for inhalation: R-343(?) – WO-2009031011 , 2009, Expert opinion on therapeutic patents.

[26]  L. Audoly,et al.  Cartilage preservation by inhibition of Janus kinase 3 in two rodent models of rheumatoid arthritis , 2008, Arthritis research & therapy.

[27]  J. Krieglstein,et al.  Reversible Phosphorylation of Histidine Residues in Proteins from Vertebrates , 2009, Science Signaling.

[28]  D. Schwarzer,et al.  Protein kinase structure and function analysis with chemical tools. , 2005, Biochimica et biophysica acta.

[29]  R. Davis,et al.  Signal Transduction by the JNK Group of MAP Kinases , 2000, Cell.

[30]  G. Chan,et al.  Double-blind, placebo-controlled, dose-escalation study to evaluate the pharmacologic effect of CP-690,550 in patients with psoriasis. , 2009, The Journal of investigative dermatology.

[31]  J. D. Di Santo,et al.  Tyrosine kinase SYK: essential functions for immunoreceptor signalling. , 2000, Immunology today.

[32]  W. Sandborn,et al.  Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. , 2012, The New England journal of medicine.

[33]  M. Weinblatt,et al.  Treatment of rheumatoid arthritis with a Syk kinase inhibitor: a twelve-week, randomized, placebo-controlled trial. , 2008, Arthritis and rheumatism.

[34]  K. Asadullah,et al.  Protein kinases as small molecule inhibitor targets in inflammation. , 2007, Current medicinal chemistry.

[35]  Victor L. J. Tybulewicz,et al.  The SYK tyrosine kinase: a crucial player in diverse biological functions , 2010, Nature Reviews Immunology.

[36]  H. Schaeffer,et al.  Mitogen-Activated Protein Kinases: Specific Messages from Ubiquitous Messengers , 1999, Molecular and Cellular Biology.

[37]  M. Karin,et al.  Mammalian MAP kinase signalling cascades , 2001, Nature.

[38]  M. Reth Antigen receptor tail clue , 1989, Nature.

[39]  P. Dobrzanski,et al.  The many faces of Janus kinase. , 2012, Biochemical pharmacology.

[40]  David Gruben,et al.  The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. , 2009, Arthritis and rheumatism.

[41]  J. Crawford,et al.  Activation of tyrosine kinases in cancer. , 2003, The oncologist.

[42]  Kathleen M. Smith,et al.  Development, cytokine profile and function of human interleukin 17–producing helper T cells , 2007, Nature Immunology.

[43]  D. Gary Gilliland,et al.  Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders , 2007, Nature Reviews Cancer.

[44]  H. Nakamura,et al.  Molecular cloning of a porcine gene syk that encodes a 72-kDa protein-tyrosine kinase showing high susceptibility to proteolysis. , 1991, The Journal of biological chemistry.

[45]  J. Woodgett,et al.  The stress-activated protein kinase pathways , 1999, Cellular and Molecular Life Sciences CMLS.

[46]  A. Chaudhary,et al.  Tyrosine kinase Syk associates with toll‐like receptor 4 and regulates signaling in human monocytic cells , 2007, Immunology and cell biology.

[47]  N. Gray,et al.  Targeting cancer with small molecule kinase inhibitors , 2009, Nature Reviews Cancer.

[48]  A. Edelman,et al.  Protein serine/threonine kinases. , 1987, Annual review of biochemistry.

[49]  H. Weedon,et al.  Expression of Jak3, STAT1, STAT4, and STAT6 in inflammatory arthritis: unique Jak3 and STAT4 expression in dendritic cells in seropositive rheumatoid arthritis , 2005, Annals of the rheumatic diseases.

[50]  R. Mesa Ruxolitinib, a selective JAK1 and JAK2 inhibitor for the treatment of myeloproliferative neoplasms and psoriasis. , 2010, IDrugs : the investigational drugs journal.

[51]  W. Leonard,et al.  Jaks and STATs: biological implications. , 1998, Annual review of immunology.

[52]  L. Notarangelo,et al.  Jak3, severe combined immunodeficiency, and a new class of immunosuppressive drugs , 2005, Immunological reviews.

[53]  B. Aggarwal,et al.  TNF Activates Syk Protein Tyrosine Kinase Leading to TNF-Induced MAPK Activation, NF-κB Activation, and Apoptosis1 , 2004, The Journal of Immunology.

[54]  B. Reitz,et al.  Effects of JAK3 Inhibition with CP-690,550 on Immune Cell Populations and Their Functions in Nonhuman Primate Recipients of Kidney Allografts , 2005, Transplantation.

[55]  John J. O’Shea,et al.  Modulation of Innate and Adaptive Immune Responses by Tofacitinib (CP-690,550) , 2011, The Journal of Immunology.

[56]  C. Balagué,et al.  Understanding autoimmune disease: new targets for drug discovery. , 2009, Drug discovery today.

[57]  A. Manning,et al.  Jun N-terminal kinase in rheumatoid arthritis. , 1999, The Journal of pharmacology and experimental therapeutics.

[58]  Lawrence Steinman,et al.  Optimization of current and future therapy for autoimmune diseases , 2012, Nature Medicine.

[59]  Stanley B. Cohen,et al.  A 24-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study of the Efficacy of Oral SCIO-469, a p38 Mitogen-activated Protein Kinase Inhibitor, in Patients with Active Rheumatoid Arthritis , 2011, The Journal of Rheumatology.

[60]  J. Darnell,et al.  Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. , 1994, Science.

[61]  J. Johnston,et al.  Molecular cloning of L-JAK, a Janus family protein-tyrosine kinase expressed in natural killer cells and activated leukocytes. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[62]  T. Kurosaki Regulation of B cell fates by BCR signaling components. , 2002, Current opinion in immunology.

[63]  T. Cheng,et al.  Evaluation of the efficacy and safety of pamapimod, a p38 MAP kinase inhibitor, in a double-blind, methotrexate-controlled study of patients with active rheumatoid arthritis. , 2009, Arthritis and rheumatism.

[64]  S. Bhagwat,et al.  Kinase inhibitors for the treatment of inflammatory and autoimmune disorders , 2008, Purinergic Signalling.

[65]  D E Griswold,et al.  Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function. , 1996, The Journal of pharmacology and experimental therapeutics.

[66]  J. Avruch,et al.  Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. , 2001, Physiological reviews.

[67]  E. Krebs 1 The Enzymology of Control by Phosphorylation , 1986 .

[68]  M. Genovese,et al.  An oral spleen tyrosine kinase (Syk) inhibitor for rheumatoid arthritis. , 2010, The New England journal of medicine.

[69]  S. Krautwald IL-16 activates the SAPK signaling pathway in CD4+ macrophages. , 1998, Journal of immunology.

[70]  R. Caspi,et al.  Th1 and Th17 cells , 2010, Annals of the New York Academy of Sciences.

[71]  G. Stark,et al.  How cells respond to interferons. , 1998, Annual review of biochemistry.

[72]  G. Firestein,et al.  Mitogen activated protein kinase inhibitors: where are we now and where are we going? , 2006, Annals of the rheumatic diseases.

[73]  W. Robinson,et al.  A multitude of kinases--which are the best targets in treating rheumatoid arthritis? , 2010, Rheumatic diseases clinics of North America.

[74]  S. Meloche,et al.  Atypical mitogen-activated protein kinases: structure, regulation and functions. , 2007, Biochimica et biophysica acta.

[75]  O. McCarty,et al.  GPVI and integrin αIIbβ3 signaling in platelets , 2005, Journal of thrombosis and haemostasis : JTH.

[76]  Tamas Koncz,et al.  Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial , 2013, The Lancet.

[77]  J. O’Shea,et al.  Prevention of Organ Allograft Rejection by a Specific Janus Kinase 3 Inhibitor , 2003, Science.

[78]  S. Rane,et al.  JAK3: a novel JAK kinase associated with terminal differentiation of hematopoietic cells. , 1994, Oncogene.

[79]  K. Sada,et al.  Structure and function of Syk protein-tyrosine kinase. , 2001, Journal of biochemistry.

[80]  Charles Peterfy,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. , 2011, Arthritis and rheumatism.

[81]  Maarten Boers,et al.  Syk kinase inhibitors for rheumatoid arthritis: trials and tribulations. , 2011, Arthritis and rheumatism.

[82]  P. Changelian,et al.  The Novel JAK‐3 Inhibitor CP‐690550 Is a Potent Immunosuppressive Agent in Various Murine Models , 2004, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[83]  D. Hommes,et al.  Inhibition of stress-activated MAP kinases induces clinical improvement in moderate to severe Crohn's disease. , 2002, Gastroenterology.

[84]  P. Tak,et al.  A Novel Spleen Tyrosine Kinase Inhibitor Blocks c-Jun N-Terminal Kinase-Mediated Gene Expression in Synoviocytes , 2006, Journal of Pharmacology and Experimental Therapeutics.

[85]  Qingbo Xu,et al.  Activation, differential localization, and regulation of the stress-activated protein kinases, extracellular signal-regulated kinase, c-JUN N-terminal kinase, and p38 mitogen-activated protein kinase, in synovial tissue and cells in rheumatoid arthritis. , 2000, Arthritis and rheumatism.

[86]  K. Shokat,et al.  The evolution of protein kinase inhibitors from antagonists to agonists of cellular signaling. , 2011, Annual review of biochemistry.

[87]  W. Leonard Role of Jak Kinases and STATs in Cytokine Signal Transduction , 2001, International journal of hematology.

[88]  J. Cambier New nomenclature for the Reth motif (or ARH1/TAM/ARAM/YXXL) , 1995, Immunology today.

[89]  B. Strober,et al.  Effect of tofacitinib, a Janus kinase inhibitor, on haematological parameters during 12 weeks of psoriasis treatment , 2013, The British journal of dermatology.

[90]  J. O’Shea,et al.  Janus kinases in immune cell signaling , 2009, Immunological reviews.

[91]  P. Rutgeerts,et al.  A randomised placebo-controlled multicentre trial of intravenous semapimod HCl for moderate to severe Crohn's disease , 2010, Gut.

[92]  T. Robak,et al.  Tyrosine kinase inhibitors as potential drugs for B-cell lymphoid malignancies and autoimmune disorders , 2012, Expert opinion on investigational drugs.

[93]  C. Widmann,et al.  Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. , 1999, Physiological reviews.

[94]  D. Payan,et al.  Targeting Syk as a treatment for allergic and autoimmune disorders , 2004, Expert opinion on investigational drugs.

[95]  J. Telliez,et al.  Engagement of Tumor Necrosis Factor (TNF) Receptor 1 Leads to ATF-2- and p38 Mitogen-activated Protein Kinase-dependent TNF-α Gene Expression* , 1999, The Journal of Biological Chemistry.

[96]  A. Mócsai,et al.  Syk is required for integrin signaling in neutrophils. , 2002, Immunity.

[97]  J. O’Shea,et al.  Therapeutic targeting of Janus kinases , 2008, Immunological reviews.

[98]  S. Grant Therapeutic Protein Kinase Inhibitors , 2009, Cellular and Molecular Life Sciences.

[99]  A. Manning,et al.  Targeting JNK for therapeutic benefit: from junk to gold? , 2003, Nature Reviews Drug Discovery.

[100]  I. Melnikova,et al.  Targeting protein kinases , 2004, Nature Reviews Drug Discovery.