2XP2

Structure of the Human Anaplastic Lymphoma Kinase in Complex with Crizotinib (PF-02341066)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.207 
  • R-Value Observed: 0.207 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Structure Based Drug Design of Crizotinib (Pf-02341066), a Potent and Selective Dual Inhibitor of Mesenchymal-Epithelial Transition Factor (C-met) Kinase and Anaplastic Lymphoma Kinase (Alk).

Cui, J.J.Tran-Dube, M.Shen, H.Nambu, M.Kung, P.P.Pairish, M.Jia, L.Meng, J.Funk, L.Botrous, I.Mctigue, M.Grodsky, N.Ryan, K.Padrique, E.Alton, G.Timofeevski, S.Yamazaki, S.Li, Q.Zou, H.Christensen, J.Mroczkowski, B.Bender, S.Kania, R.S.Edwards, M.P.

(2011) J Med Chem 54: 6342

  • DOI: https://doi.org/10.1021/jm2007613
  • Primary Citation of Related Structures:  
    2WGJ, 2WKM, 2XP2

  • PubMed Abstract: 

    Because of the critical roles of aberrant signaling in cancer, both c-MET and ALK receptor tyrosine kinases are attractive oncology targets for therapeutic intervention. The cocrystal structure of 3 (PHA-665752), bound to c-MET kinase domain, revealed a novel ATP site environment, which served as the target to guide parallel, multiattribute drug design. A novel 2-amino-5-aryl-3-benzyloxypyridine series was created to more effectively make the key interactions achieved with 3. In the novel series, the 2-aminopyridine core allowed a 3-benzyloxy group to reach into the same pocket as the 2,6-dichlorophenyl group of 3 via a more direct vector and thus with a better ligand efficiency (LE). Further optimization of the lead series generated the clinical candidate crizotinib (PF-02341066), which demonstrated potent in vitro and in vivo c-MET kinase and ALK inhibition, effective tumor growth inhibition, and good pharmaceutical properties.


  • Organizational Affiliation

    La Jolla Laboratories, Pfizer Worldwide Research and Development, San Diego, California 92121, USA. [email protected]


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
TYROSINE-PROTEIN KINASE RECEPTOR327Homo sapiensMutation(s): 0 
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q9UM73 (Homo sapiens)
Explore Q9UM73 
Go to UniProtKB:  Q9UM73
PHAROS:  Q9UM73
GTEx:  ENSG00000171094 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9UM73
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
VGH
Query on VGH

Download Ideal Coordinates CCD File 
B [auth A]3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)pyridin-2-amine
C21 H22 Cl2 F N5 O
KTEIFNKAUNYNJU-GFCCVEGCSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
VGH BindingDB:  2XP2 Ki: min: 0.74, max: 8.2 (nM) from 2 assay(s)
Kd: min: 3.3, max: 4.4 (nM) from 2 assay(s)
IC50: min: 0.64, max: 3039 (nM) from 78 assay(s)
EC50: min: 575, max: 2.28e+4 (nM) from 3 assay(s)
PDBBind:  2XP2 IC50: 1 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.207 
  • R-Value Observed: 0.207 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 51.633α = 90
b = 57.086β = 90
c = 104.709γ = 90
Software Package:
Software NamePurpose
CNSrefinement
XDSdata reduction
SCALAdata scaling
CNSphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-09-15
    Type: Initial release
  • Version 1.1: 2011-09-28
    Changes: Database references, Structure summary, Version format compliance
  • Version 1.2: 2019-05-08
    Changes: Data collection, Experimental preparation, Other
  • Version 1.3: 2019-05-15
    Changes: Data collection, Experimental preparation
  • Version 1.4: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description