7Q7K

JAK2 in complex with 4-(2-amino-8-methoxyquinazolin-6-yl)phenol

7Q7K の概要

• エントリーDOI: 10.2210/pdb7q7k/pdb
• 分子名称: Tyrosine-protein kinase JAK2, 4-(2-azanyl-8-methoxy-quinazolin-6-yl)phenol (3 entities in total)
• 機能のキーワード: jak2, janus kinase 2, signaling protein
• 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: 37721.58

構造登録者

Rowland, P. (登録日: 2021-11-09, 公開日: 2022-02-02, 最終更新日: 2024-10-23)

主引用文献

Wellaway, C.R.,Baldwin, I.R.,Bamborough, P.,Barker, D.,Bartholomew, M.A.,Chung, C.W.,Dumpelfeld, B.,Evans, J.P.,Fazakerley, N.J.,Homes, P.,Keeling, S.P.,Lewell, X.Q.,McNab, F.W.,Morley, J.,Needham, D.,Neu, M.,van Oosterhout, A.J.M.,Pal, A.,Reinhard, F.B.M.,Rianjongdee, F.,Robertson, C.M.,Rowland, P.,Shah, R.R.,Sherriff, E.B.,Sloan, L.A.,Teague, S.,Thomas, D.A.,Wellaway, N.,Wojno-Picon, J.,Woolven, J.M.,Coe, D.M.
Investigation of Janus Kinase (JAK) Inhibitors for Lung Delivery and the Importance of Aldehyde Oxidase Metabolism.
J.Med.Chem., 65:633-664, 2022

PubMed Abstract: The Janus family of tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) play an essential role in the receptor signaling of cytokines that have been implicated in the pathogenesis of severe asthma, and there is emerging interest in the development of small-molecule-inhaled JAK inhibitors as treatments. Here, we describe the optimization of a quinazoline series of JAK inhibitors and the results of mouse lung pharmacokinetic (PK) studies where only low concentrations of parent compound were observed. Subsequent investigations revealed that the low exposure was due to metabolism by aldehyde oxidase (AO), so we sought to identify quinazolines that were not metabolized by AO. We found that specific substituents at the quinazoline 2-position prevented AO metabolism and this was rationalized through computational docking studies in the AO binding site, but they compromised kinome selectivity. Results presented here highlight that AO metabolism is a potential issue in the lung.

PubMed: 34928601
DOI: 10.1021/acs.jmedchem.1c01765

実験手法

X-RAY DIFFRACTION (1.61 Å)