3ZTX

Aurora kinase selective inhibitors identified using a Taxol-induced checkpoint sensitivity screen.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.226 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.188 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.0 of the entry. See complete history


Literature

Selective Aurora Kinase Inhibitors Identified Using a Taxol- Induced Checkpoint Sensitivity Screen.

Kwiatkowski, N.Deng, X.Wang, J.Tan, L.Villa, F.Santaguida, S.Huang, H.C.Mitchison, T.Musacchio, A.Gray, N.

(2012) ACS Chem Biol 7: 185

  • DOI: https://doi.org/10.1021/cb200305u
  • Primary Citation of Related Structures:  
    3ZTX

  • PubMed Abstract: 

    The members of the Aurora kinase family play critical roles in the regulation of the cell cycle and mitotic spindle assembly and have been intensively investigated as potential targets for a new class of anticancer drugs. We describe a new highly potent and selective class of Aurora kinase inhibitors discovered using a phenotypic cellular screen. Optimized inhibitors display many of the hallmarks of Aurora inhibition including endoreduplication, polyploidy, and loss of cell viability in cancer cells. Structure-activity relationships with respect to kinome-wide selectivity and guided by an Aurora B co-crystal structure resulted in the identification of key selectivity determinants and discovery of a subseries with selectivity toward Aurora A. A direct comparison of biochemical and cellular profiles with respect to published Aurora inhibitors including VX-680, AZD1152, MLN8054, and a pyrimidine-based compound from Genentech demonstrates that compounds 1 and 3 will become valuable additional pharmacological probes of Aurora-dependent functions.


  • Organizational Affiliation

    Department of Cancer Biology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
SERINE/THREONINE-PROTEIN KINASE 12-A
A, B
284Xenopus laevisMutation(s): 0 
EC: 2.7.11.1
UniProt
Find proteins for Q6DE08 (Xenopus laevis)
Explore Q6DE08 
Go to UniProtKB:  Q6DE08
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ6DE08
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
INNER CENTROMERE PROTEIN A
C, D
44Xenopus laevisMutation(s): 0 
UniProt
Find proteins for O13024 (Xenopus laevis)
Explore O13024 
Go to UniProtKB:  O13024
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO13024
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
ZTX
Query on ZTX

Download Ideal Coordinates CCD File 
E [auth A],
F [auth B]
2-((4-(4-HYDROXYPIPERIDIN-1-YL)PHENYL)AMINO)-5,11-DIMETHYL-5H-BENZO[E]PYRIMIDO [5,4-B][1,4]DIAZEPIN-6(11H)-ONE
C24 H26 N6 O2
DFQAJLQXPSPNJE-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
TPO
Query on TPO
A, B
L-PEPTIDE LINKINGC4 H10 N O6 PTHR
Binding Affinity Annotations 
IDSourceBinding Affinity
ZTX PDBBind:  3ZTX IC50: 18.4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.226 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.188 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 45.634α = 90
b = 66.364β = 96.56
c = 116.679γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-02-01
    Type: Initial release