4DEI

Crystal structure of c-Met in complex with triazolopyridinone inhibitor 24

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.05 Å
  • R-Value Free: 0.289 
  • R-Value Work: 0.221 
  • R-Value Observed: 0.224 

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This is version 1.2 of the entry. See complete history. 


Literature

Discovery and optimization of a potent and selective triazolopyridinone series of c-Met inhibitors.

Bode, C.M., Boezio, A.A., Albrecht, B.K., Bellon, S.F., Berry, L., Broome, M.A., Choquette, D., Dussault, I., Lewis, R.T., Lin, M.H., Rex, K., Whittington, D.A., Yang, Y., Harmange, J.C.

(2012) Bioorg Med Chem Lett 22: 4089-4093

  • DOI: https://doi.org/10.1016/j.bmcl.2012.04.072
  • Primary Citation of Related Structures:  
    4DEG, 4DEH, 4DEI

  • PubMed Abstract: 

    Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is an attractive target for small molecule drug discovery. Herein, we report the discovery of a structurally diverse series of carbon-linked quinoline triazolopyridinones, which demonstrates nanomolar inhibition of c-Met kinase activity. This novel series of inhibitors exhibits favorable pharmacokinetics as well as potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver pharmacodynamic model.

    • Organizational Affiliation: 

    Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA. aboezio@amgen.com


Macromolecules
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(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Hepatocyte growth factor receptor309Homo sapiensMutation(s): 0 
Gene Names: MET
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for P08581 (Homo sapiens)
Explore P08581 
Go to UniProtKB:  P08581
PHAROS:  P08581
GTEx:  ENSG00000105976 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP08581
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
0JL
Query on 0JL
Download Ideal Coordinates CCD File 
B [auth A]3-{(1S)-1-[3-(2-methoxyethoxy)quinolin-6-yl]ethyl}-5-(3-methyl-1,2-thiazol-5-yl)-3,5-dihydro-4H-[1,2,3]triazolo[4,5-c]pyridin-4-one
C23 H22 N6 O3 S
ACDVIHRBYWUYPZ-HNNXBMFYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
0JL Binding MOAD:  4DEI IC50: 1 (nM) from 1 assay(s)
BindingDB:  4DEI IC50: min: 0.6, max: 2 (nM) from 3 assay(s)
PDBBind:  4DEI IC50: 1 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.05 Å
  • R-Value Free: 0.289 
  • R-Value Work: 0.221 
  • R-Value Observed: 0.224 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.788α = 90
b = 42.592β = 90
c = 158.2γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
CrystalCleardata collection
DENZOdata reduction

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: 2012-05-30
    Type: Initial release
  • Version 1.1: 2012-06-20
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations