Bifunctional Ligands for Inhibition of Tight-Binding Protein-Protein Interactions

Bioconjug Chem. 2016 Aug 17;27(8):1900-10. doi: 10.1021/acs.bioconjchem.6b00293. Epub 2016 Jul 20.


The acknowledged potential of small-molecule therapeutics targeting disease-related protein-protein interactions (PPIs) has promoted active research in this field. The strategy of using small molecule inhibitors (SMIs) to fight strong (tight-binding) PPIs tends to fall short due to the flat and wide interfaces of PPIs. Here we propose a biligand approach for disruption of strong PPIs. The potential of this approach was realized for disruption of the tight-binding (KD = 100 pM) tetrameric holoenzyme of cAMP-dependent protein kinase (PKA). Supported by X-ray analysis of cocrystals, bifunctional inhibitors (ARC-inhibitors) were constructed that simultaneously associated with both the ATP-pocket and the PPI interface area of the catalytic subunit of PKA (PKAc). Bifunctional inhibitor ARC-1411, possessing a KD value of 3 pM toward PKAc, induced the dissociation of the PKA holoenzyme with a low-nanomolar IC50, whereas the ATP-competitive inhibitor H89 bound to the PKA holoenzyme without disruption of the protein tetramer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic AMP-Dependent Protein Kinases / chemistry
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Fluorescent Dyes / chemistry
  • Ligands
  • Models, Molecular
  • Protein Binding / drug effects
  • Protein Conformation
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / metabolism*
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Purines / chemistry
  • Purines / metabolism*
  • Purines / pharmacology*
  • rho-Associated Kinases / antagonists & inhibitors


  • 7-deazapurine
  • Fluorescent Dyes
  • Ligands
  • Protein Kinase Inhibitors
  • Purines
  • Proto-Oncogene Proteins c-akt
  • rho-Associated Kinases
  • Cyclic AMP-Dependent Protein Kinases