6TFP

BTK in complex with LOU064, a potent and highly selective covalent inhibitor

6TFP の概要

• エントリーDOI: 10.2210/pdb6tfp/pdb
• 分子名称: Tyrosine-protein kinase BTK, SODIUM ION, ~{N}-[3-[6-azanyl-5-[2-[methyl(propanoyl)amino]ethoxy]pyrimidin-4-yl]-5-fluoranyl-2-methyl-phenyl]-4-cyclopropyl-2-fluoranyl-benzamide, ... (4 entities in total)
• 機能のキーワード: btk, complex, inhibitor, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 162652.30

構造登録者

Scheufler, C.,Hinniger, A.,Gutmann, S. (登録日: 2019-11-14, 公開日: 2020-03-04, 最終更新日: 2024-11-06)

主引用文献

Angst, D.,Gessier, F.,Janser, P.,Vulpetti, A.,Walchli, R.,Beerli, C.,Littlewood-Evans, A.,Dawson, J.,Nuesslein-Hildesheim, B.,Wieczorek, G.,Gutmann, S.,Scheufler, C.,Hinniger, A.,Zimmerlin, A.,Funhoff, E.G.,Pulz, R.,Cenni, B.
Discovery of LOU064 (Remibrutinib), a Potent and Highly Selective Covalent Inhibitor of Bruton's Tyrosine Kinase.
J.Med.Chem., 63:5102-5118, 2020

PubMed Abstract: Bruton's tyrosine kinase (BTK), a cytoplasmic tyrosine kinase, plays a central role in immunity and is considered an attractive target for treating autoimmune diseases. The use of currently marketed covalent BTK inhibitors is limited to oncology indications based on their suboptimal kinase selectivity. We describe the discovery and preclinical profile of LOU064 (remibrutinib, ), a potent, highly selective covalent BTK inhibitor. LOU064 exhibits an exquisite kinase selectivity due to binding to an inactive conformation of BTK and has the potential for a best-in-class covalent BTK inhibitor for the treatment of autoimmune diseases. It demonstrates potent target occupancy with an EC of 1.6 mg/kg and dose-dependent efficacy in rat collagen-induced arthritis. LOU064 is currently being tested in phase 2 clinical studies for chronic spontaneous urticaria and Sjoegren's syndrome.

PubMed: 32083858
DOI: 10.1021/acs.jmedchem.9b01916

実験手法

X-RAY DIFFRACTION (2 Å)