6HRT

CRYSTAL STRUCTURE OF BTK KINASE DOMAIN COMPLEXED WITH 12-(6-tert-butyl-8-fluoro-1-oxo-phthalazin-2-yl)-9-hydroxy-6-methyl-4-[[5-(morpholine-4-carbonyl)-2-pyridyl]amino]-6-azatricyclo[9.4.0.02,7]pentadeca-1(15),2(7),3,11,13-pentaen-5-one

6HRT の概要

• エントリーDOI: 10.2210/pdb6hrt/pdb
• 関連するPDBエントリー: 6HRP
• 分子名称: Tyrosine-protein kinase BTK, (9~{S})-12-(6-~{tert}-butyl-8-fluoranyl-1-oxidanylidene-phthalazin-2-yl)-6-methyl-4-[(5-morpholin-4-ylcarbonylpyridin-2-yl)amino]-9-oxidanyl-6-azatricyclo[9.4.0.0^{2,7}]pentadeca-1(15),2(7),3,11,13-pentaen-5-one (3 entities in total)
• 機能のキーワード: transferase-transferase inhibitor complex, transferase
• 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: 33185.86

構造登録者

Kuglstatter, A.,Janson, C. (登録日: 2018-09-28, 公開日: 2019-03-20, 最終更新日: 2024-05-15)

主引用文献

Lopez-Tapia, F.,Lou, Y.,Brotherton-Pleiss, C.,Kuglstatter, A.,So, S.S.,Kondru, R.
A potent seven-membered cyclic BTK (Bruton's tyrosine Kinase) chiral inhibitor conceived by structure-based drug design to lock its bioactive conformation.
Bioorg.Med.Chem.Lett., 29:1074-1078, 2019

PubMed Abstract: A seven-membered cyclic chiral analog of potent lead BTK inhibitor 1 was envisioned by structure-based design to lock the molecule into its bioactive conformation. For the elaboration of the seven-membered ring, compound 1 pyridone 6-position was substituted with the purpose to prevent formation of reactive metabolites. Eventually, the cyclic chiral compound 3 maintained the high potency of 1, and most importantly showed no activity at either GSH or TDI assays suggesting no formation of reactive metabolites. The anticipated bound conformation of 3 to BTK was confirmed by X-ray crystallography. Synthetically, the crucial seven-membered ring formation was obtained by using TosMIC as a connective reagent.

PubMed: 30857747
DOI: 10.1016/j.bmcl.2019.03.001

実験手法

X-RAY DIFFRACTION (1.36 Å)