title: Bifunctional Ligands for Inhibition of Tight-Binding Protein-Protein Interactions.
abstract: 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.
authors.affiliation: Institute of Chemistry, University of Tartu , 50410 Tartu, Estonia.
authors.forename: Taavi
authors.initials: T
authors.lastname: Ivan
authors.affiliation: Institute of Chemistry, University of Tartu , 50410 Tartu, Estonia.
authors.forename: Erki
authors.initials: E
authors.lastname: Enkvist
authors.affiliation: Institute of Chemistry, University of Tartu , 50410 Tartu, Estonia.
authors.forename: Birgit
authors.initials: B
authors.lastname: Viira
authors.affiliation: Institute of Chemistry, University of Tartu , 50410 Tartu, Estonia.
authors.forename: Ganesh Babu
authors.initials: GB
authors.lastname: Manoharan
authors.affiliation: Institute of Chemistry, University of Tartu , 50410 Tartu, Estonia.
authors.forename: Gerda
authors.initials: G
authors.lastname: Raidaru
authors.affiliation: The Norwegian Structural Biology Centre, Department of Chemistry, University of Tromsø , N-9019 Tromsø, Norway.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pflug
authors.affiliation: The Norwegian Structural Biology Centre, Department of Chemistry, University of Tromsø , N-9019 Tromsø, Norway.
authors.forename: Kazi Asraful
authors.initials: KA
authors.lastname: Alam
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford , OX1 3QX Oxford, United Kingdom.
authors.forename: Manuela
authors.initials: M
authors.lastname: Zaccolo
authors.affiliation: The Norwegian Structural Biology Centre, Department of Chemistry, University of Tromsø , N-9019 Tromsø, Norway.
authors.forename: Richard Alan
authors.initials: RA
authors.lastname: Engh
authors.affiliation: Institute of Chemistry, University of Tartu , 50410 Tartu, Estonia.
authors.forename: Asko
authors.initials: A
authors.lastname: Uri
mesh_terms: D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D005456:Fluorescent Dyes / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D011687:Purines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
chemical_list: C512929:7-deazapurine; D005456:Fluorescent Dyes; D008024:Ligands; D047428:Protein Kinase Inhibitors; D011687:Purines; D051057:Proto-Oncogene Proteins c-akt; D054460:rho-Associated Kinases; D017868:Cyclic AMP-Dependent Protein Kinases