6D22

Crystal structure of Tyrosine-protein kinase receptor

Summary for 6D22

• Entry DOI: 10.2210/pdb6d22/pdb
• Descriptor: Tyrosine-protein kinase receptor (2 entities in total)
• Functional Keywords: allostric inhibitor tyrosine kinase, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 34970.36

Authors

Greasley, S.E.,Brown, D. (deposition date: 2018-04-12, release date: 2018-05-02, Last modification date: 2024-03-13)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.46 Å)