6W06

Bruton's tyrosine kinase in complex with compound 6

6W06 の概要

• エントリーDOI: 10.2210/pdb6w06/pdb
• 関連するPDBエントリー: 6VXQ
• 分子名称: Tyrosine-protein kinase BTK, DIMETHYL SULFOXIDE, 2,3-DIHYDROXY-1,4-DITHIOBUTANE, ... (5 entities in total)
• 機能のキーワード: kinase, transferase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34513.72

構造登録者

Metrick, C.M.,Marcotte, D.J. (登録日: 2020-02-29, 公開日: 2020-12-16, 最終更新日: 2023-10-11)

主引用文献

Ma, B.,Bohnert, T.,Otipoby, K.L.,Tien, E.,Arefayene, M.,Bai, J.,Bajrami, B.,Bame, E.,Chan, T.R.,Humora, M.,MacPhee, J.M.,Marcotte, D.,Mehta, D.,Metrick, C.M.,Moniz, G.,Polack, E.,Poreci, U.,Prefontaine, A.,Sheikh, S.,Schroeder, P.,Smirnakis, K.,Zhang, L.,Zheng, F.,Hopkins, B.T.
Discovery of BIIB068: A Selective, Potent, Reversible Bruton's Tyrosine Kinase Inhibitor as an Orally Efficacious Agent for Autoimmune Diseases.
J.Med.Chem., 63:12526-12541, 2020

PubMed Abstract: Autoreactive B cell-derived antibodies form immune complexes that likely play a pathogenic role in autoimmune diseases. In systemic lupus erythematosus (SLE), these antibodies bind Fc receptors on myeloid cells and induce proinflammatory cytokine production by monocytes and NETosis by neutrophils. Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase that signals downstream of Fc receptors and plays a transduction role in antibody expression following B cell activation. Given the roles of BTK in both the production and sensing of autoreactive antibodies, inhibitors of BTK kinase activity may provide therapeutic value to patients suffering from autoantibody-driven immune disorders. Starting from an in-house proprietary screening hit followed by structure-based rational design, we have identified a potent, reversible BTK inhibitor, BIIB068 (), which demonstrated good kinome selectivity with good overall drug-like properties for oral dosing, was well tolerated across preclinical species at pharmacologically relevant doses with good ADME properties, and achieved >90% inhibition of BTK phosphorylation (pBTK) in humans.

PubMed: 32696648
DOI: 10.1021/acs.jmedchem.0c00702

実験手法

X-RAY DIFFRACTION (1.55 Å)