6DKB

Crystal structure of Trk-A in complex with the Pan-Trk Kinase Inhibitor, compound 10b.

Summary for 6DKB

• Entry DOI: 10.2210/pdb6dkb/pdb
• Descriptor: High affinity nerve growth factor receptor, 2-{[(3R,4S)-3-fluoro-1-{[4-(trifluoromethoxy)phenyl]acetyl}piperidin-4-yl]oxy}-5-(1-methyl-1H-imidazol-4-yl)pyridine-3-carboxamide (3 entities in total)
• Functional Keywords: inhibitor tyrosine kinase, transferase, pan-trk kinase, treatment for pain, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 36631.97

Authors

Greasley, S.E.,Johnson, E.,Kraus, M.L.,Cronin, C.N. (deposition date: 2018-05-29, release date: 2018-07-11, Last modification date: 2024-03-13)

Primary citation

Bagal, S.K.,Andrews, M.,Bechle, B.M.,Bian, J.,Bilsland, J.,Blakemore, D.C.,Braganza, J.F.,Bungay, P.J.,Corbett, M.S.,Cronin, C.N.,Cui, J.J.,Dias, R.,Flanagan, N.J.,Greasley, S.E.,Grimley, R.,James, K.,Johnson, E.,Kitching, L.,Kraus, M.L.,McAlpine, I.,Nagata, A.,Ninkovic, S.,Omoto, K.,Scales, S.,Skerratt, S.E.,Sun, J.,Tran-Dube, M.,Waldron, G.J.,Wang, F.,Warmus, J.S.
Discovery of Potent, Selective, and Peripherally Restricted Pan-Trk Kinase Inhibitors for the Treatment of Pain.
J. Med. Chem., 61:6779-6800, 2018

PubMed Abstract: Hormones of the neurotrophin family, nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), are known to activate the family of Tropomyosin receptor kinases (TrkA, TrkB, and TrkC). Moreover, inhibition of the TrkA kinase pathway in pain has been clinically validated by the NGF antibody tanezumab, leading to significant interest in the development of small molecule inhibitors of TrkA. Furthermore, Trk inhibitors having an acceptable safety profile will require minimal brain availability. Herein, we discuss the discovery of two potent, selective, peripherally restricted, efficacious, and well-tolerated series of pan-Trk inhibitors which successfully delivered three candidate quality compounds 10b, 13b, and 19. All three compounds are predicted to possess low metabolic clearance in human that does not proceed via aldehyde oxidase-catalyzed reactions, thus addressing the potential clearance prediction liability associated with our current pan-Trk development candidate PF-06273340.

PubMed: 29944371
DOI: 10.1021/acs.jmedchem.8b00633

Experimental method

X-RAY DIFFRACTION (2.68 Å)