4XMO

Crystal structure of c-Met in complex with (R)-5-(8-fluoro-3-(1-fluoro-1-(3-methoxyquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-methylisoxazole


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.189 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Discovery of Potent and Selective 8-Fluorotriazolopyridine c-Met Inhibitors.

Peterson, E.A.Teffera, Y.Albrecht, B.K.Bauer, D.Bellon, S.F.Boezio, A.Boezio, C.Broome, M.A.Choquette, D.Copeland, K.W.Dussault, I.Lewis, R.Lin, M.H.Lohman, J.Liu, J.Potashman, M.Rex, K.Shimanovich, R.Whittington, D.A.Vaida, K.R.Harmange, J.C.

(2015) J Med Chem 58: 2417-2430

  • DOI: https://doi.org/10.1021/jm501913a
  • Primary Citation of Related Structures:  
    4XMO, 4XYF

  • PubMed Abstract: 

    The overexpression of c-Met and/or hepatocyte growth factor (HGF), the amplification of the MET gene, and mutations in the c-Met kinase domain can activate signaling pathways that contribute to cancer progression by enabling tumor cell proliferation, survival, invasion, and metastasis. Herein, we report the discovery of 8-fluorotriazolopyridines as inhibitors of c-Met activity. Optimization of the 8-fluorotriazolopyridine scaffold through the combination of structure-based drug design, SAR studies, and metabolite identification provided potent (cellular IC50 < 10 nM), selective inhibitors of c-Met with desirable pharmacokinetic properties that demonstrate potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver pharmacodynamic model.


  • Organizational Affiliation

    Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.


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
46G
Query on 46G

Download Ideal Coordinates CCD File 
B [auth A]6-{(1R)-1-fluoro-1-[8-fluoro-6-(3-methyl-1,2-oxazol-5-yl)[1,2,4]triazolo[4,3-a]pyridin-3-yl]ethyl}-3-methoxyquinoline
C22 H17 F2 N5 O2
WIXYFSZDBHGKBE-JOCHJYFZSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
46G BindingDB:  4XMO IC50: min: 2, max: 3 (nM) from 2 assay(s)
Binding MOAD:  4XMO IC50: 2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.238 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.189 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.951α = 90
b = 43.395β = 90
c = 157.974γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
PDB_EXTRACTdata extraction
REFMACrefinement
CrystalCleardata collection

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-03-11
    Type: Initial release
  • Version 1.1: 2015-03-25
    Changes: Database references
  • Version 1.2: 2017-11-22
    Changes: Database references, Derived calculations, Refinement description, Source and taxonomy
  • Version 1.3: 2024-02-28
    Changes: Data collection, Database references