Structural basis for inhibition of Eg5 by dihydropyrimidines: stereoselectivity of antimitotic inhibitors enastron, dimethylenastron and fluorastrol

J Med Chem. 2010 Aug 12;53(15):5676-83. doi: 10.1021/jm100421n.

Abstract

Human kinesin Eg5, which plays an essential role in mitosis by establishing the bipolar spindle, has proven to be an interesting drug target for the development of cancer chemotherapeutics. Here, we report the crystal structures of the Eg5 motor domain complexed with enastron, dimethylenastron, and fluorastrol. By comparing these structures to that of monastrol and mon-97, we identified the main reasons for increased potency of these new inhibitors, namely the better fit of the ligand to the allosteric binding site and the addition of fluorine atoms. We also noticed preferential binding of the S-enantiomer of enastron and dimethylenastron to Eg5, while the R-enantiomer of fluorastrol binds preferentially to Eg5. In addition, we performed a multidrug resistance (MDR) study in cell lines overexpressing P-glycoprotein (Pgp). We showed that one of these inhibitors may have the potential to overcome susceptibility to this efflux pump and hence overcome common resistance associated with tubulin-targeting drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis
  • Antimitotic Agents / chemical synthesis
  • Antimitotic Agents / chemistry*
  • Antimitotic Agents / pharmacology
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Drug Resistance, Multiple
  • Humans
  • Kinesins / antagonists & inhibitors*
  • Kinesins / chemistry
  • Models, Molecular
  • Protein Conformation
  • Protein Structure, Tertiary
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry*
  • Quinazolines / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thiones / chemical synthesis
  • Thiones / chemistry*
  • Thiones / pharmacology

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antimitotic Agents
  • KIF11 protein, human
  • Pyrimidines
  • Quinazolines
  • Thiones
  • dimethylenastron
  • enastron
  • fluorastrol
  • Kinesins

Associated data

  • PDB/2X7C
  • PDB/2X7D
  • PDB/2X7E