title: 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.
abstract: BACKGROUND
  Spleen tyrosine kinase (SYK) is a key integrator of intracellular signals triggered by activated immunoreceptors, including Bcell receptors (BCR) and Fc receptors, which are important for the development and function of lymphoid cells. Given the clinical efficacy of Bcell depletion in the treatment of rheumatoid arthritis and multiple sclerosis, pharmacological modulation of Bcells using orally active small molecules that selectively target SYK presents an attractive alternative therapeutic strategy.
  
  
  METHODS
  A SYK inhibitor was developed and assayed in various in vitro systems and in the mouse model of collagen-induced arthritis (mCIA).
  
  
  RESULTS
  A novel ATP-competitive inhibitor of SYK, 6-[(1R,2S)-2-Amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide, designated RO9021, with an adequate kinase selectivity profile and oral bioavailability, was developed. In addition to suppression of BCR signaling in human peripheral blood mononuclear cells (PBMC) and whole blood, FcγR signaling in human monocytes, and FcϵR signaling in human mast cells, RO9021 blocked osteoclastogenesis from mouse bone marrow macrophages in vitro. Interestingly, Toll-like Receptor (TLR) 9 signaling in human Bcells was inhibited by RO9021, resulting in decreased levels of plasmablasts, immunoglobulin (Ig) M and IgG upon B-cell differentiation. RO9021 also potently inhibited type I interferon production by human plasmacytoid dendritic cells (pDC) upon TLR9 activation. This effect is specific to TLR9 as RO9021 did not inhibit TLR4- or JAK-STAT-mediated signaling. Finally, oral administration of RO9021 inhibited arthritis progression in the mCIA model, with observable pharmacokinetics (PK)-pharmacodynamic (PD) correlation.
  
  
  CONCLUSIONS
  Inhibition of SYK kinase activity impinges on various innate and adaptive immune responses. RO9021 could serve as a starting point for the development of selective SYK inhibitors for the treatment of inflammation-related and autoimmune-related disorders.
authors.forename: Cheng
authors.initials: C
authors.lastname: Liao
authors.forename: Jonathan
authors.initials: J
authors.lastname: Hsu
authors.forename: Yong
authors.initials: Y
authors.lastname: Kim
authors.forename: Dong-Qing
authors.initials: DQ
authors.lastname: Hu
authors.forename: Daigen
authors.initials: D
authors.lastname: Xu
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Achal
authors.initials: A
authors.lastname: Pashine
authors.forename: John
authors.initials: J
authors.lastname: Menke
authors.forename: Toni
authors.initials: T
authors.lastname: Whittard
authors.forename: Natasha
authors.initials: N
authors.lastname: Romero
authors.forename: Theresa
authors.initials: T
authors.lastname: Truitt
authors.forename: Michelle
authors.initials: M
authors.lastname: Slade
authors.forename: Christine
authors.initials: C
authors.lastname: Lukacs
authors.forename: Johannes
authors.initials: J
authors.lastname: Hermann
authors.forename: Mingyan
authors.initials: M
authors.lastname: Zhou
authors.forename: Matthew
authors.initials: M
authors.lastname: Lucas
authors.forename: Satwant
authors.initials: S
authors.lastname: Narula
authors.forename: Julie
authors.initials: J
authors.lastname: DeMartino
authors.forename: Seng-Lai
authors.initials: SL
authors.lastname: Tan
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects*; D000284:Administration, Oral; D000631:Aminopyridines / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism / Q000517:prevention & control; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005434:Flow Cytometry; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D019169:Jurkat Cells; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008958:Models, Molecular; D015394:Molecular Structure; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000072377:Syk Kinase
chemical_list: C000590133:6-(2-aminocyclohexylamino)-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxylic acid amide; D000631:Aminopyridines; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D054852:Small Molecule Libraries; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse