4AOJ

Human TrkA in complex with the inhibitor AZ-23

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.75 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.221 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history. 


Literature

Discovery of Disubstituted Imidazo[4,5-B]Pyridines and Purines as Potent Trka Inhibitors

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.

(2012) ACS Med Chem Lett 3: 705

  • DOI: https://doi.org/10.1021/ml300074j
  • Primary Citation of Related Structures:  
    4AOJ

  • 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.

    • Organizational Affiliation: 

    Oncology Innovative Medicines Unit, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.


Macromolecules
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(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HIGH AFFINITY NERVE GROWTH FACTOR RECEPTOR
A, B, C
329Homo sapiensMutation(s): 0 
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for P04629 (Homo sapiens)
Explore P04629 
Go to UniProtKB:  P04629
PHAROS:  P04629
GTEx:  ENSG00000198400 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP04629
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
V4Z
Query on V4Z
Download Ideal Coordinates CCD File 
D [auth A],
G [auth B],
J [auth C]		5-chloranyl-N2-[(1S)-1-(5-fluoranylpyridin-2-yl)ethyl]-N4-(3-propan-2-yloxy-1H-pyrazol-5-yl)pyrimidine-2,4-diamine
C17 H19 Cl F N7 O
LBVKEEFIPBQIMD-JTQLQIEISA-N
ZN
Query on ZN
Download Ideal Coordinates CCD File 
E [auth A]
F [auth A]
H [auth B]
I [auth B]
K [auth C]
E [auth A],
F [auth A],
H [auth B],
I [auth B],
K [auth C],
L [auth C]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
V4Z BindingDB:  4AOJ Ki: min: 0.36, max: 3.7 (nM) from 2 assay(s)
Kd: 2 (nM) from 1 assay(s)
IC50: min: 0.26, max: 9.9 (nM) from 9 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.75 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.221 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 130.727α = 90
b = 158.419β = 90
c = 152.577γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-08-15
    Type: Initial release
  • Version 1.1: 2012-10-31
    Changes: Database references
  • Version 1.2: 2014-06-18
    Changes: Database references
  • Version 1.3: 2019-05-08
    Changes: Data collection, Experimental preparation, Other
  • Version 1.4: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description