2OO8

Synthesis, Structural Analysis, and SAR Studies of Triazine Derivatives as Potent, Selective Tie-2 Inhibitors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.279 
  • R-Value Work: 0.233 
  • R-Value Observed: 0.235 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Synthesis, structural analysis, and SAR studies of triazine derivatives as potent, selective Tie-2 inhibitors.

Hodous, B.L.Geuns-Meyer, S.D.Hughes, P.E.Albrecht, B.K.Bellon, S.Caenepeel, S.Cee, V.J.Chaffee, S.C.Emery, M.Fretland, J.Gallant, P.Gu, Y.Johnson, R.E.Kim, J.L.Long, A.M.Morrison, M.Olivieri, P.R.Patel, V.F.Polverino, A.Rose, P.Wang, L.Zhao, H.

(2007) Bioorg Med Chem Lett 17: 2886-2889

  • DOI: https://doi.org/10.1016/j.bmcl.2007.02.067
  • Primary Citation of Related Structures:  
    2OO8, 2OSC

  • PubMed Abstract: 

    A novel class of selective Tie-2 inhibitors was derived from a multi-kinase inhibitor 1. By reversing the amide connectivity and incorporating aminotriazine or aminopyridine hinge-binding moieties, excellent Tie-2 potency and KDR selectivity could be achieved with 3-substituted terminal aryl rings. X-ray co-crystal structure analysis aided inhibitor design. This series was evaluated on the basis of potency, selectivity, and rat pharmacokinetic parameters.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, MA 02139, USA. bhodous@amgen.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Angiopoietin-1 receptorA [auth X]317Homo sapiensMutation(s): 0 
Gene Names: TEKTIE2
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q02763 (Homo sapiens)
Explore Q02763 
Go to UniProtKB:  Q02763
PHAROS:  Q02763
GTEx:  ENSG00000120156 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ02763
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
RAJ
Query on RAJ

Download Ideal Coordinates CCD File 
B [auth X]N-{3-[3-(DIMETHYLAMINO)PROPYL]-5-(TRIFLUOROMETHYL)PHENYL}-4-METHYL-3-[(3-PYRIMIDIN-4-YLPYRIDIN-2-YL)AMINO]BENZAMIDE
C29 H29 F3 N6 O
OHHGYJBFPVJURR-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
RAJ Binding MOAD:  2OO8 IC50: 1 (nM) from 1 assay(s)
BindingDB:  2OO8 IC50: 1 (nM) from 1 assay(s)
PDBBind:  2OO8 IC50: 1 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.279 
  • R-Value Work: 0.233 
  • R-Value Observed: 0.235 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 62.604α = 90
b = 62.604β = 90
c = 181.043γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
CrystalCleardata collection
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2007-03-20
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2023-12-27
    Changes: Data collection, Database references, Derived calculations