4DCE

Crystal structure of human anaplastic lymphoma kinase in complex with a piperidine-carboxamide inhibitor

4DCE の概要

• エントリーDOI: 10.2210/pdb4dce/pdb
• 分子名称: ALK tyrosine kinase receptor, (3S)-N-(4-methylbenzyl)-1-{2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}piperidine-3-carboxamide (3 entities in total)
• 機能のキーワード: receptor tyrosine kinase, inhibitor, npm-alk, eml4-alk, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cell membrane ; Single-pass type I membrane protein : Q9UM73
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 76119.43

構造登録者

Whittington, D.A.,Epstein, L.F.,Chen, H. (登録日: 2012-01-17, 公開日: 2012-02-08, 最終更新日: 2024-04-03)

主引用文献

Bryan, M.C.,Whittington, D.A.,Doherty, E.M.,Falsey, J.R.,Cheng, A.C.,Emkey, R.,Brake, R.L.,Lewis, R.T.
Rapid development of piperidine carboxamides as potent and selective anaplastic lymphoma kinase inhibitors.
J.Med.Chem., 55:1698-1705, 2012

PubMed Abstract: Piperidine carboxamide 1 was identified as a novel inhibitor of anaplastic lymphoma kinase (ALK enzyme assay IC(50) = 0.174 μM) during high throughput screening, with selectivity over the related kinase insulin-like growth factor-1 (IGF1R). The X-ray cocrystal structure of 1 with the ALK kinase domain revealed an unusual DFG-shifted conformation, allowing access to an extended hydrophobic pocket. Structure-activity relationship (SAR) studies were focused on the rapid parallel optimization of both the right- and left-hand side of the molecule, culminating in molecules with improved potency and selectivity over IGF1R.

PubMed: 22263917
DOI: 10.1021/jm201565s

実験手法

X-RAY DIFFRACTION (2.03 Å)