5EYM

MEK1 IN COMPLEX WITH BI 847325


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.308 
  • R-Value Work: 0.243 
  • R-Value Observed: 0.247 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 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
Dual specificity mitogen-activated protein kinase kinase 1
A, B
359Homo sapiensMutation(s): 3 
Gene Names: MAP2K1MEK1PRKMK1
EC: 2.7.12.2
UniProt & NIH Common Fund Data Resources
Find proteins for Q02750 (Homo sapiens)
Explore Q02750 
Go to UniProtKB:  Q02750
PHAROS:  Q02750
GTEx:  ENSG00000169032 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ02750
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
5U5 BindingDB:  5EYM IC50: 25 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.308 
  • R-Value Work: 0.243 
  • R-Value Observed: 0.247 
  • Space Group: P 61
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 78.76α = 90
b = 78.76β = 90
c = 223.412γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
XSCALEdata 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: 2016-08-17
    Type: Initial release
  • Version 1.1: 2016-10-19
    Changes: Database references
  • Version 1.2: 2024-01-10
    Changes: Data collection, Database references, Derived calculations, Refinement description