5EYK

CRYSTAL STRUCTURE OF AURORA B IN COMPLEX WITH BI 847325


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.93 Å
  • R-Value Free: 0.222 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.200 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Pharmacological Profile of BI 847325, an Orally Bioavailable, ATP-Competitive Inhibitor of MEK and Aurora Kinases.

Sini, P.Gurtler, U.Zahn, S.K.Baumann, C.Rudolph, D.Baumgartinger, R.Strauss, E.Haslinger, C.Tontsch-Grunt, U.Waizenegger, I.C.Solca, F.Bader, G.Zoephel, A.Treu, M.Reiser, U.Garin-Chesa, P.Boehmelt, G.Kraut, N.Quant, J.Adolf, G.R.

(2016) Mol Cancer Ther 15: 2388-2398

  • DOI: https://doi.org/10.1158/1535-7163.MCT-16-0066
  • Primary Citation of Related Structures:  
    5EYK, 5EYM, 5K3Y

  • PubMed Abstract: 

    Although the MAPK pathway is frequently deregulated in cancer, inhibitors targeting RAF or MEK have so far shown clinical activity only in BRAF- and NRAS-mutant melanoma. Improvements in efficacy may be possible by combining inhibition of mitogenic signal transduction with inhibition of cell-cycle progression. We have studied the preclinical pharmacology of BI 847325, an ATP-competitive dual inhibitor of MEK and Aurora kinases. Potent inhibition of MEK1/2 and Aurora A/B kinases by BI 847325 was demonstrated in enzymatic and cellular assays. Equipotent effects were observed in BRAF-mutant cells, whereas in KRAS-mutant cells, MEK inhibition required higher concentrations than Aurora kinase inhibition. Daily oral administration of BI 847325 at 10 mg/kg showed efficacy in both BRAF- and KRAS-mutant xenograft models. Biomarker analysis suggested that this effect was primarily due to inhibition of MEK in BRAF-mutant models but of Aurora kinase in KRAS-mutant models. Inhibition of both MEK and Aurora kinase in KRAS-mutant tumors was observed when BI 847325 was administered once weekly at 70 mg/kg. Our studies indicate that BI 847325 is effective in in vitro and in vivo models of cancers with BRAF and KRAS mutation. These preclinical data are discussed in the light of the results of a recently completed clinical phase I trial assessing safety, tolerability, pharmacokinetics, and efficacy of BI 847325 in patients with cancer. Mol Cancer Ther; 15(10); 2388-98. ©2016 AACR.


  • Organizational Affiliation

    Department of Pharmacology and Translational Research, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria. patrizia.sini@boehringer-ingelheim.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Aurora kinase B-A
A, B
276Xenopus laevisMutation(s): 1 
Gene Names: aurkb-aairk2-a
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
59Xenopus laevisMutation(s): 0 
Gene Names: incenp-a
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
5U5
Query on 5U5

Download Ideal Coordinates CCD File 
E [auth A],
F [auth B]
3-[(3~{Z})-3-[[[4-[(dimethylamino)methyl]phenyl]amino]-phenyl-methylidene]-2-oxidanylidene-1~{H}-indol-6-yl]-~{N}-ethyl-prop-2-ynamide
C29 H28 N4 O2
FLBNLJLONKAPLR-DQSJHHFOSA-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
5U5 BindingDB:  5EYK IC50: 3 (nM) from 1 assay(s)
Binding MOAD:  5EYK IC50: 3 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.93 Å
  • R-Value Free: 0.222 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.200 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 46.14α = 90
b = 67.45β = 96.63
c = 116.76γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
XSCALEdata scaling
PDB_EXTRACTdata extraction
XDSdata reduction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-08-17
    Type: Initial release
  • Version 1.1: 2016-10-19
    Changes: Database references