5JFV

Crystal structure of TrkA in complex with PF-05206283

Summary for 5JFV

• Entry DOI: 10.2210/pdb5jfv/pdb
• Related: 5JFS 5JFW 5JFX
• Descriptor: 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)
• Functional Keywords: trka inhibitor complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane ; Single-pass type I membrane protein : P04629
• Total number of polymer chains: 1
• Total formula weight: 35550.46

Authors

Jayasankar, J.,Kurumbail, R.,Brown, D.,Skerratt, S. (deposition date: 2016-04-19, release date: 2017-03-01, Last modification date: 2024-03-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.59 Å)