5JFV

Crystal structure of TrkA in complex with PF-05206283

5JFV の概要

• エントリーDOI: 10.2210/pdb5jfv/pdb
• 関連するPDBエントリー: 5JFS 5JFW 5JFX
• 分子名称: High affinity nerve growth factor receptor, N-{5-[4-amino-7-(propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]pyridin-3-yl}-2-(4-chlorophenyl)acetamide (3 entities in total)
• 機能のキーワード: trka inhibitor complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase 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 : P04629
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35550.46

構造登録者

Jayasankar, J.,Kurumbail, R.,Brown, D.,Skerratt, S. (登録日: 2016-04-19, 公開日: 2017-03-01, 最終更新日: 2024-03-06)

主引用文献

Skerratt, S.E.,Andrews, M.,Bagal, S.K.,Bilsland, J.,Brown, D.,Bungay, P.J.,Cole, S.,Gibson, K.R.,Jones, R.,Morao, I.,Nedderman, A.,Omoto, K.,Robinson, C.,Ryckmans, T.,Skinner, K.,Stupple, P.,Waldron, G.
The Discovery of a Potent, Selective, and Peripherally Restricted Pan-Trk Inhibitor (PF-06273340) for the Treatment of Pain.
J. Med. Chem., 59:10084-10099, 2016

PubMed Abstract: The neurotrophin family of growth factors, comprised of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), is implicated in the physiology of chronic pain. Given the clinical efficacy of anti-NGF monoclonal antibody (mAb) therapies, there is significant interest in the development of small molecule modulators of neurotrophin activity. Neurotrophins signal through the tropomyosin related kinase (Trk) family of tyrosine kinase receptors, hence Trk kinase inhibition represents a potentially "druggable" point of intervention. To deliver the safety profile required for chronic, nonlife threatening pain indications, highly kinase-selective Trk inhibitors with minimal brain availability are sought. Herein we describe how the use of SBDD, 2D QSAR models, and matched molecular pair data in compound design enabled the delivery of the highly potent, kinase-selective, and peripherally restricted clinical candidate PF-06273340.

PubMed: 27766865
DOI: 10.1021/acs.jmedchem.6b00850

実験手法

X-RAY DIFFRACTION (1.59 Å)