CHAPTER 10:Bruton's Tyrosine Kinase (Btk)

Bruton's tyrosine kinase (Btk) is a non-receptor tyrosine kinase belonging to the Tec family of kinases. Btk is critical for B-cell development, differentiation and signalling through the B-cell antigen receptor (BCR) as is evident by its genetic association to a human primary immunodeficiency disease known as X-linked Agammaglobulinemia (XLA). Btk is also present in specific cells of the myeloid lineage and contributes to the activation of the FcγR and FceR signalling pathways in macrophages, neutrophils and mast cells. Because of its key role in these pathways, Btk is considered a promising target for therapeutic intervention in autoimmune and inflammatory disease. Numerous research groups are actively working to identify Btk inhibitors through the targeting of inactive kinase conformations or covalent active site inhibition. Both strategies have benefited from the rapid growth in structural biology insight for the target. Recently discovered potent and orally bioavailable Btk inhibitors have shown promising efficacy in several pre-clinical animal models of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). These results, coupled with promising initial findings from the study of Btk inhibitors in human clinical trials for oncology, strongly suggest Btk intervention offers significant potential as a treatment strategy in inflammatory disease.