4AOJ

Human TrkA in complex with the inhibitor AZ-23

Summary for 4AOJ

• Entry DOI: 10.2210/pdb4aoj/pdb
• Related: 1HE7 1SHC 1WWA 1WWW
• Descriptor: HIGH AFFINITY NERVE GROWTH FACTOR RECEPTOR, 5-chloranyl-N2-[(1S)-1-(5-fluoranylpyridin-2-yl)ethyl]-N4-(3-propan-2-yloxy-1H-pyrazol-5-yl)pyrimidine-2,4-diamine, ZINC ION, ... (4 entities in total)
• Functional Keywords: transferase, inhibitor
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 3
• Total formula weight: 112263.08

Authors

Wang, T.,Lamb, M.L.,Block, M.H.,Davies, A.M.,Han, Y.,Hoffmann, E.,Ioannidis, S.,Josey, J.A.,Liu, Z.,Lyne, P.D.,MacIntyre, T.,Mohr, P.J.,Omer, C.A.,Sjogren, T.,Thress, K.,Wang, B.,Wang, H.,Yu, D.,Zhang, H. (deposition date: 2012-03-28, release date: 2012-08-15, Last modification date: 2023-12-20)

Primary citation

Wang, T.,Lamb, M.L.,Block, M.H.,Davies, A.M.,Han, Y.,Hoffmann, E.,Ioannidis, S.,Josey, J.A.,Liu, Z.,Lyne, P.D.,Macintyre, T.,Mohr, P.J.,Omer, C.A.,Sjogren, T.,Thress, K.,Wang, B.,Wang, H.,Yu, D.,Zhang, H.
Discovery of Disubstituted Imidazo[4,5-B]Pyridines and Purines as Potent Trka Inhibitors
Acs Med.Chem.Lett., 3:705-, 2012

PubMed Abstract: Trk receptor tyrosine kinases have been implicated in cancer and pain. A crystal structure of TrkA with AZ-23 (1a) was obtained, and scaffold hopping resulted in two 5/6-bicyclic series comprising either imidazo[4,5-b]pyridines or purines. Further optimization of these two fusion series led to compounds with subnanomolar potencies against TrkA kinase in cellular assays. Antitumor effects in a TrkA-driven mouse allograft model were demonstrated with compounds 2d and 3a.

PubMed: 24900538
DOI: 10.1021/ML300074J

Experimental method

X-RAY DIFFRACTION (2.75 Å)