Bifunctional ligands for inhibition of tightbinding

Journal article

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 co-crystals, bifunctional inhibitors (ARC-inhibitors) were constructed that simultaneously associated with both the ATP-pocket and PPI interface area of the catalytic subunit of PKA (PKAc). Bifunctional inhibitor ARC-1411, possessing KD value of 3 pM towards 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.

Authors: Ivan, T; Enkvist, E; Viira, B; Manoharan, G; Raidaru, G

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Chemical Society
• Journal: Bioconjugate Chemistry
• Volume: 27
• Issue: 8
• Pages: 1900–1910
• Publication date: 2016-07-01
• Acceptance date: 2016-07-07
• DOI: 10.1021/acs.bioconjchem.6b00293
• ISSN: 1520-4812
• Keywords: tight-binding; PKA holoenzyme; bifunctional ligand; bisubstrate; inhibitor; protein kinase; Protein-protein interaction; fluorescent probe; fluorescence anisotropy