Design of potent protein kinase inhibitors using the bisubstrate approach

J Med Chem. 1991 Jan;34(1):73-8. doi: 10.1021/jm00105a012.


A new class of serine/threonine protein kinase inhibitors was designed by associating, in the same structure, mimics of both the ATP binding site and a protein substrate. Among the several potent antagonists which were obtained, the most active consists of isoquinoline-5-sulfonamide, as ATP mimic, and Ser-Arg6, as peptidic moiety, bound by a-NH(CH2)2NH(CH2)2CO-linker. This compound, with a Ki of 0.1 microM toward protein kinase C (PKC) and 0.004 microM toward cyclic AMP dependent protein kinase (PKA), is respectively 60- and 750-fold more active than the commercial inhibitor H-7.

Publication types

  • Comparative Study

MeSH terms

  • Adenosine Triphosphate / analogs & derivatives*
  • Adenosine Triphosphate / metabolism
  • Binding Sites
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Isoquinolines / chemical synthesis*
  • Isoquinolines / chemistry
  • Isoquinolines / pharmacology
  • Kinetics
  • Molecular Structure
  • Protein Kinase C / antagonists & inhibitors*
  • Protein Kinase Inhibitors*
  • Structure-Activity Relationship
  • Substrate Specificity
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology


  • Enzyme Inhibitors
  • Isoquinolines
  • Protein Kinase Inhibitors
  • Sulfonamides
  • Adenosine Triphosphate
  • Protein Kinase C