6S90

BTK in complex with an inhibitor

6S90 の概要

• エントリーDOI: 10.2210/pdb6s90/pdb
• 分子名称: Tyrosine-protein kinase BTK, 4-~{tert}-butyl-~{N}-[2-methyl-3-[6-[4-(4-methylpiperazin-1-yl)carbonylphenyl]-7~{H}-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]benzamide (3 entities in total)
• 機能のキーワード: btk, bruton tyrosine kinase, agammaglobulinaemia tyrosine kinase, atk, b-cell progenitor kinase, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 63415.01

構造登録者

Gutmann, S.,Hinniger, A. (登録日: 2019-07-11, 公開日: 2019-09-18, 最終更新日: 2024-05-15)

主引用文献

Pulz, R.,Angst, D.,Dawson, J.,Gessier, F.,Gutmann, S.,Hersperger, R.,Hinniger, A.,Janser, P.,Koch, G.,Revesz, L.,Vulpetti, A.,Waelchli, R.,Zimmerlin, A.,Cenni, B.
Design of Potent and Selective Covalent Inhibitors of Bruton's Tyrosine Kinase Targeting an Inactive Conformation.
Acs Med.Chem.Lett., 10:1467-1472, 2019

PubMed Abstract: Bruton's tyrosine kinase (BTK) is a member of the TEC kinase family and is selectively expressed in a subset of immune cells. It is a key regulator of antigen receptor signaling in B cells and of Fc receptor signaling in mast cells and macrophages. A BTK inhibitor will likely have a positive impact on autoimmune diseases which are caused by autoreactive B cells and immune-complex driven inflammation. We report the design, optimization, and characterization of potent and selective covalent BTK inhibitors. Starting from the selective reversible inhibitor binding to an inactive conformation of BTK, we designed covalent irreversible compounds by attaching an electrophilic warhead to reach Cys481. The first prototype covalently modified BTK and showed an excellent kinase selectivity including several Cys-containing kinases, validating the design concept. In addition, this compound blocked FcγR-mediated hypersensitivity . Optimization of whole blood potency and metabolic stability resulted in compounds such as , which maintained the excellent kinase selectivity and showed improved BTK occupancy .

PubMed: 31620235
DOI: 10.1021/acsmedchemlett.9b00317

実験手法

X-RAY DIFFRACTION (1.82 Å)