title: Targeting the SYK-BTK axis for the treatment of immunological and hematological disorders: recent progress and therapeutic perspectives.
abstract: Spleen Tyrosine Kinase (SYK) and Bruton's Tyrosine Kinase (BTK) are non-receptor cytoplasmic tyrosine kinases that are primarily expressed in cells of hematopoietic lineage. Both are key mediators in coupling activated immunoreceptors to downstream signaling events that affect diverse biological functions, from cellular proliferation, differentiation and adhesion to innate and adaptive immune responses. As such, pharmacological inhibitors of SYK or BTK are being actively pursued as potential immunomodulatory agents for the treatment of autoimmune and inflammatory disorders. Deregulation of SYK or BTK activity has also been implicated in certain hematological malignancies. To date, from a clinical perspective, pharmacological inhibition of SYK activity has demonstrated encouraging efficacy in patients with rheumatoid arthritis (RA), while patients with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) have benefited from covalent inhibitors of BTK in early clinical studies. Here, we review and discuss recent insights into the emerging role of the SYK-BTK axis in innate immune cell function as well as in the maintenance of survival and homing signals for tumor cell progression. The current progress on the clinical development of SYK and BTK inhibitors is also highlighted.
authors: Inflammation Discovery and Therapeutic Area, Hoffmann-La Roche, Nutley, NJ 07110, USA. tsltan@yahoo.com
authors: Seng-Lai
authors: SL
authors: Tan
authors: Cheng
authors: C
authors: Liao
authors: Matthew C
authors: MC
authors: Lucas
authors: Christopher
authors: C
authors: Stevenson
authors: Julie A
authors: JA
authors: DeMartino
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D006402:Hematologic Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D006801:Humans; D007154:Immune System Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D007113:Immunity, Innate / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D000072377:Syk Kinase
chemical_list: D000276:Adjuvants, Immunologic; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000606896:SYK protein, human; D000072377:Syk Kinase