Targeting large kinase active site with rigid, bulky octahedral ruthenium complexes

J Am Chem Soc. 2008 Nov 26;130(47):15764-5. doi: 10.1021/ja805555a.


A strategy for targeting protein kinases with large ATP-binding sites by using bulky and rigid octahedral ruthenium complexes as structural scaffolds is presented. A highly potent and selective GSK3 and Pim1 half-sandwich complex NP309 was successfully converted into a PAK1 inhibitor by making use of the large octahedral compounds Lambda-FL172 and Lambda-FL411 in which the cyclopentadienyl moiety of NP309 is replaced by a chloride and sterically demanding diimine ligands. A 1.65 A cocrystal structure of PAK1 with Lambda-FL172 reveals how the large coordination sphere of the ruthenium complex matches the size of the active site and serves as a yardstick to discriminate between otherwise closely related binding sites.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Catalytic Domain
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Inhibitory Concentration 50
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinases / chemistry*
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Rats
  • Ruthenium Compounds / chemical synthesis
  • Ruthenium Compounds / chemistry*
  • Ruthenium Compounds / pharmacology
  • Substrate Specificity


  • Protein Kinase Inhibitors
  • Ruthenium Compounds
  • Protein Kinases