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

Taavi Ivan, Erki Enkvist, Birgit Viira, Ganesh Babu Manoharan, Gerda Raidaru, Alexander Pflug, Kazi Asraful Alam, Manuela Zaccolo, Richard Alan Engh, Asko Uri*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

19 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1900-1910
Number of pages11
JournalBioconjugate Chemistry
Issue number8
Publication statusPublished - 17 Aug 2016
Externally publishedYes


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