B-Cell Receptor Signaling Inhibitors for Treatment of Autoimmune Inflammatory Diseases and B-Cell Malignancies

Abstract

B-cell receptor (BCR) signaling is essential for normal B-cell development, selection, survival, proliferation, and differentiation into antibody-secreting cells. Similarly, this pathway plays a key role in the pathogenesis of multiple B-cell malignancies. Genetic and pharmacological approaches have established an important role for the spleen tyrosine kinase (Syk), Bruton's tyrosine kinase (Btk), and phosphatidylinositol 3-kinase isoform p110delta (PI3Kδ) in coupling the BCR and other receptors on B cells to B-cell survival, migration, and activation. In the past few years, several small-molecule inhibitory drugs that target PI3Kδ, Btk, and Syk have been developed and shown to have efficacy in clinical trials for the treatment of several types of B-cell malignancies and inflammatory diseases. Emerging preclinical and clinical data have also shown a critical role of BCR signaling in the activation and function of self-reactive B cells that contribute to autoimmune diseases. Because BCR signaling plays a major role in both B-cell-mediated autoimmune inflammation and B-cell malignancies, inhibition of this pathway may represent a promising new strategy for treating these diseases. This review summarizes recent achievements in understanding the mechanism of action, pharmacological properties, and clinical activity and toxicity of these BCR signaling inhibitors, with a focus on their emerging role in treating lymphoid malignancies and autoimmune disorders.

Keywords :

• Btk
• autoimmunity
• CGI1746
• chronic lymphocytic leukemia
• fostamatinib (R788)
• ibrutinib (PCI-32765)
• IC87114
• idelalisib (GS-1101
• CAL-101)
• non-Hodgkin lymphoma
• p110δ
• Syk
• phosphoinositide 3-kinase