Ibrutinib inhibition of Bruton protein-tyrosine kinase (BTK) in the treatment of B cell neoplasms

摘要: The Bruton non-receptor protein-tyrosine kinase (BTK), a deficiency of which leads to X-linked agammaglobulinemia, plays central role in B cell antigen receptor signaling. Owing the exclusivity this enzyme cells, acronym could represent tyrosine kinase. BTK is activated by Lyn and SYK protein kinases following activation receptor. turn catalyzes phosphorylation phospholipase Cγ2 leading downstream Ras/RAF/MEK/ERK pathway NF-κB pathways. Both pathways participate maturation antibody-producing cells. domains include PH (pleckstrin homology) domain that interacts with membrane-associated phosphatidyl inositol trisphosphate, TH (TEC domain, followed an SH3, SH2, finally domain. Dysregulation signaling occurs several neoplasms including mantle lymphoma, chronic lymphocytic leukemia, Waldenstrom macroglobulinemia. Ibrutinib FDA-approved as first-line or second line treatment for these diseases. drug binds tightly ATP-binding pocket making salt bridges residues within hinge connects two lobes enzyme; then its unsaturated acrylamide group forms covalent bond cysteine 481 form inactive adduct. In addition various lymphomas, ibrutinib under clinical trials numerous solid tumors owing tumor-promoting inflammation pathogenesis neoplastic