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

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

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Institute of Chemistry, University of Tartu , 50410 Tartu, Estonia.
The Norwegian Structural Biology Centre, Department of Chemistry, University of Tromsø , N-9019 Tromsø, Norway.
Department of Physiology, Anatomy and Genetics, University of Oxford , OX1 3QX Oxford, United Kingdom.


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.

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