4DEE

Aurora A in complex with ADP


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.259 
  • R-Value Work: 0.213 
  • R-Value Observed: 0.213 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Development of o-Chlorophenyl Substituted Pyrimidines as Exceptionally Potent Aurora Kinase Inhibitors.

Lawrence, H.R.Martin, M.P.Luo, Y.Pireddu, R.Yang, H.Gevariya, H.Ozcan, S.Zhu, J.Y.Kendig, R.Rodriguez, M.Elias, R.Cheng, J.Q.Sebti, S.M.Schonbrunn, E.Lawrence, N.J.

(2012) J Med Chem 55: 7392-7416

  • DOI: https://doi.org/10.1021/jm300334d
  • Primary Citation of Related Structures:  
    3UP7, 4DEA, 4DEB, 4DED, 4DEE

  • PubMed Abstract: 

    The o-carboxylic acid substituted bisanilinopyrimidine 1 was identified as a potent hit (Aurora A IC(50) = 6.1 ± 1.0 nM) from in-house screening. Detailed structure-activity relationship (SAR) studies indicated that polar substituents at the para position of the B-ring are critical for potent activity. X-ray crystallography studies revealed that compound 1 is a type I inhibitor that binds the Aurora kinase active site in a DFG-in conformation. Structure-activity guided replacement of the A-ring carboxylic acid with halogens and incorporation of fluorine at the pyrimidine 5-position led to highly potent inhibitors of Aurora A that bind in a DFG-out conformation. B-Ring modifications were undertaken to improve the solubility and cell permeability. Compounds such as 9m with water-solubilizing moieties at the para position of the B-ring inhibited the autophosphorylation of Aurora A in MDA-MB-468 breast cancer cells.


  • Organizational Affiliation

    Department of Drug Discovery, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Aurora kinase A279Homo sapiensMutation(s): 1 
Gene Names: AURKAAIKAIRK1ARK1AURAAYK1BTAKIAK1STK15STK6
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for O14965 (Homo sapiens)
Explore O14965 
Go to UniProtKB:  O14965
PHAROS:  O14965
GTEx:  ENSG00000087586 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO14965
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.259 
  • R-Value Work: 0.213 
  • R-Value Observed: 0.213 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 81.11α = 90
b = 81.11β = 90
c = 173.89γ = 120
Software Package:
Software NamePurpose
StructureStudiodata collection
MOLREPphasing
CNSrefinement
XDSdata reduction
XDSdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-08-22
    Type: Initial release
  • Version 1.1: 2012-09-12
    Changes: Database references
  • Version 1.2: 2012-09-26
    Changes: Database references
  • Version 1.3: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description