title: 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 BCRs 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. Emerging preclinical 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 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.
authors.affiliation: Gilead Sciences, Inc., Seattle, WA 98102, USA. kamal.puri@gilead.com
authors.forename: Kamal D
authors.initials: KD
authors.lastname: Puri
authors.forename: Julie A
authors.initials: JA
authors.lastname: Di Paolo
authors.forename: Michael R
authors.initials: MR
authors.lastname: Gold
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000378:metabolism*; D001402:B-Lymphocytes / Q000502:physiology; D006801:Humans; D015448:Leukemia, B-Cell / Q000188:drug therapy* / Q000378:metabolism*; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D011947:Receptors, Antigen, B-Cell