2P4I

Evolution of a highly Selective and Potent 2-(Pyridin-2-yl)-1,3,5-triazine Tie-2 Kinase Inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.303 
  • R-Value Work: 0.246 
  • R-Value Observed: 0.248 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Evolution of a highly selective and potent 2-(pyridin-2-yl)-1,3,5-triazine Tie-2 kinase inhibitor.

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

(2007) J Med Chem 50: 611-626

  • DOI: https://doi.org/10.1021/jm061107l
  • Primary Citation of Related Structures:  
    2P2H, 2P2I, 2P4I

  • PubMed Abstract: 

    Inhibition of angiogenesis is a promising and clinically validated approach for limiting tumor growth and survival. The receptor tyrosine kinase Tie-2 is expressed almost exclusively in the vascular endothelium and is required for developmental angiogenesis and vessel maturation. However, the significance of Tie-2 signaling in tumor angiogenesis is not well understood. In order to evaluate the therapeutic utility of inhibiting Tie-2 signaling, we developed a series of potent and orally bioavailable small molecule Tie-2 kinase inhibitors with selectivity over other kinases, especially those that are believed to be important for tumor angiogenesis. Our earlier work provided pyridinyl pyrimidine 6 as a potent, nonselective Tie-2 inhibitor that was designed on the basis of X-ray cocrystal structures of KDR inhibitors 34 (triazine) and 35 (nicotinamide). Lead optimization resulted in pyridinyl triazine 63, which exhibited >30-fold selectivity over a panel of kinases, good oral exposure, and in vivo inhibition of Tie-2 phosphorylation.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139-1581, USA. bhodous@amgen.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Angiopoietin-1 receptor
A, B
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
MR9
Query on MR9

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
4-METHYL-3-({3-[2-(METHYLAMINO)PYRIMIDIN-4-YL]PYRIDIN-2-YL}OXY)-N-[2-MORPHOLIN-4-YL-5-(TRIFLUOROMETHYL)PHENYL]BENZAMIDE
C29 H27 F3 N6 O3
HHKWHHAJTWLRKG-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
MR9 Binding MOAD:  2P4I IC50: 10 (nM) from 1 assay(s)
BindingDB:  2P4I IC50: 10 (nM) from 1 assay(s)
PDBBind:  2P4I IC50: 10 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.303 
  • R-Value Work: 0.246 
  • R-Value Observed: 0.248 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 64.262α = 90
b = 63.189β = 90
c = 175.571γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
CrystalCleardata collection
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

  • Released Date: 2007-03-20 
  • Deposition Author(s): Bellon, S.F.

Revision History  (Full details and data files)

  • Version 1.0: 2007-03-20
    Type: Initial release
  • Version 1.1: 2007-11-14
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2024-02-21
    Changes: Data collection, Database references, Derived calculations, Refinement description