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

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• 作者：Robert Roskoski Jr. ^{rrj@brimr.org" class="auth_mail" title="E-mail the corresponding author}
• 关键词：AS ; activation segment ; CLL ; chronic lymphocytic leukemia ; CS or C-spine ; catalytic spine ; CL ; catalytic loop ; HΦ or Φ ; hydrophobic ; IP3 ; inositol 1 ; 4 ; 5 trisphosphate ; IP6 ; inositol 1 ; 2 ; 3 ; 4 ; 5 ; 6 hexakisphosphate ; MCL ; mantle cell lymphoma ; MW ; molecular weight ; NSCLC ; non-small cell lung cancer ; PKA ; protein kinase A ; PIP2 ; phosphatidyl inositol 4 ; 5 bisphosphate ; PIP3 ; phosphatidyl inositol 3 ; 4 ; 5 trisphosphate ; RA ; rheumatoid arthritis ; RS or R-spine ; regulatory spine ; Sh1 ; shell residue 1 ; WM ; W
• 刊名：Pharmacological Research
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：113
• 期：part_PA
• 页码：395-408
• 全文大小：2752 K

文摘

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