MOL Highlight: Ability of Bruton’s Tyrosine Kinase Inhibitors to Sequester Y551 and Prevent Phosphorylation Determines Potency
Bruton’s tyrosine kinase (Btk) regulates signaling downstream of the B-cell receptor (BCR) and Fc receptors (FcRs). Consequently, inhibitors targeting the kinase have the potential to simultaneously block multiple disease pathways in hematopoietic cells. Here, Bender et al. characterize nine different Btk·inhibitor complexes, and show that these compounds can be classified by their ability to trigger sequestration of Btk residue Y551, which renders it inaccessible for phosphorylation. The ability to sequester Y551 was an important determinant of potency against FcR signaling, but less critical for potency against BCR signaling. The results thus delineate molecular determinants that dictate the selective effects of different classes of Btk inhibitors, and provide insight into the design new compounds with a broader inhibitory profiles that will hopefully have greater efficacy in treating disease.
See the article by Bender et al. at Molecular Pharmacology March 2017, 91 (3) 208-219; DOI: https://doi.org/10.1124/mol.116.107037