3I5N

Crystal structure of c-Met with triazolopyridazine inhibitor 13


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.267 
  • R-Value Work: 0.225 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery and optimization of potent and selective triazolopyridazine series of c-Met inhibitors

Boezio, A.A.Berry, L.Albrecht, B.K.Bauer, D.Bellon, S.F.Bode, C.Chen, A.Choquette, D.Dussault, I.Hirai, S.Kaplan-Lefko, P.Larrow, J.F.Lin, M.H.Lohman, J.Potashman, M.H.Rex, K.Santostefano, M.Shah, K.Shimanovich, R.Springer, S.K.Teffera, Y.Yang, Y.Zhang, Y.Harmange, J.C.

(2009) Bioorg Med Chem Lett 19: 6307-6312

  • DOI: https://doi.org/10.1016/j.bmcl.2009.09.096
  • Primary Citation of Related Structures:  
    3I5N

  • 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. We previously showed that O-linked triazolopyridazines can be potent inhibitors of c-Met. Herein, we report the discovery of a related series of N-linked triazolopyridazines which demonstrate nanomolar inhibition of c-Met kinase activity and display improved pharmacodynamic profiles. Specifically, the potent time-dependent inhibition of cytochrome P450 associated with the O-linked triazolopyridazines has been eliminated within this novel series of inhibitors. N-linked triazolopyridazine 24 exhibited favorable pharmacokinetics and displayed potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver PD model. Once-daily oral administration of 24 for 22days showed significant tumor growth inhibition in an NIH-3T3/TPR-Met xenograft mouse efficacy model.


  • Organizational Affiliation

    Amgen Inc., One Kendall Square, Building 1000, Cambridge, MA 02139, USA; Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, 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): 1 
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
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
B2D
Query on B2D

Download Ideal Coordinates CCD File 
B [auth A]7-methoxy-N-[(6-phenyl[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl]-1,5-naphthyridin-4-amine
C21 H17 N7 O
GZLYPLRRKZCYLV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
B2D BindingDB:  3I5N IC50: min: 14, max: 17 (nM) from 2 assay(s)
PDBBind:  3I5N IC50: 14 (nM) from 1 assay(s)
Binding MOAD:  3I5N IC50: 17 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.267 
  • R-Value Work: 0.225 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.977α = 90
b = 43.241β = 90
c = 158.232γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
CrystalCleardata collection
DENZOdata reduction
AMoREphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-01-12
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description