6D20

Crystal structure of Tyrosine-protein kinase receptor in complex with 5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4(3H)-one and 5-{[2,4-dichloro-5-(pyridin-2-yl)benzene-1-carbonyl]amino}-N-(2-hydroxy-2-methylpropyl)-1-phenyl-1H-pyrazole-3-carboxamide Inhibitors

6D20 の概要

• エントリーDOI: 10.2210/pdb6d20/pdb
• 関連するPDBエントリー: 6D1Y 6D1Z
• 分子名称: High affinity nerve growth factor receptor, 5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4(3H)-one, 5-{[2,4-dichloro-5-(pyridin-2-yl)benzene-1-carbonyl]amino}-N-(2-hydroxy-2-methylpropyl)-1-phenyl-1H-pyrazole-3-carboxamide, ... (4 entities in total)
• 機能のキーワード: allosteric inhibitor complex tyrosine kinase, transferase, transferase-inhibitor complex, transferase/inhibitor
• 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: 36881.16

構造登録者

Greasley, S.E.,Johnson, E.,Kraus, M.L.,Cronin, C.N. (登録日: 2018-04-12, 公開日: 2018-05-02, 最終更新日: 2024-03-13)

主引用文献

Bagal, S.K.,Omoto, K.,Blakemore, D.C.,Bungay, P.J.,Bilsland, J.G.,Clarke, P.J.,Corbett, M.S.,Cronin, C.N.,Cui, J.J.,Dias, R.,Flanagan, N.J.,Greasley, S.E.,Grimley, R.,Johnson, E.,Fengas, D.,Kitching, L.,Kraus, M.L.,McAlpine, I.,Nagata, A.,Waldron, G.J.,Warmus, J.S.
Discovery of Allosteric, Potent, Subtype Selective, and Peripherally Restricted TrkA Kinase Inhibitors.
J. Med. Chem., 62:247-265, 2019

PubMed Abstract: Tropomyosin receptor kinases (TrkA, TrkB, TrkC) are activated by hormones of the neurotrophin family: nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4). Moreover, the NGF antibody tanezumab has provided clinical proof of concept for inhibition of the TrkA kinase pathway in pain leading to significant interest in the development of small molecule inhibitors of TrkA. However, achieving TrkA subtype selectivity over TrkB and TrkC via a Type I and Type II inhibitor binding mode has proven challenging and Type III or Type IV allosteric inhibitors may present a more promising selectivity design approach. Furthermore, TrkA inhibitors with minimal brain availability are required to deliver an appropriate safety profile. Herein, we describe the discovery of a highly potent, subtype selective, peripherally restricted, efficacious, and well-tolerated series of allosteric TrkA inhibitors that culminated in the delivery of candidate quality compound 23.

PubMed: 29672039
DOI: 10.1021/acs.jmedchem.8b00280

実験手法

X-RAY DIFFRACTION (1.94 Å)