4DEG

Crystal structure of c-Met in complex with triazolopyridazine inhibitor 2


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.254 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.209 

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Ligand Structure Quality Assessment 


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
Find similar proteins by:  (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
0JJ
Query on 0JJ

Download Ideal Coordinates CCD File 
B [auth A]7-methoxy-N-{[6-(3-methyl-1,2-thiazol-5-yl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]methyl}-1,5-naphthyridin-4-amine
C19 H16 N8 O S
QMWKLCXWSJTEFT-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
0JJ BindingDB:  4DEG Ki: 3.2 (nM) from 1 assay(s)
IC50: min: 3, max: 6 (nM) from 3 assay(s)
PDBBind:  4DEG IC50: 6 (nM) from 1 assay(s)
Binding MOAD:  4DEG IC50: 6 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.254 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.209 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.042α = 90
b = 43.012β = 90
c = 157.954γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
CrystalCleardata collection
DENZOdata reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


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