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

Ivan T, Enkvist E, Viira B, Manoharan GB, Raidaru G, Pflug A, Alam KA, Zaccolo M, Engh RA, Uri A
Bioconjug Chem 27 1900-10 (2016)
Related entries: 5izf, 5izj

Cited: 8 times
EuropePMC logo PMID: 27389935

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.

Reviews citing this publication (1)

  1. Photoresponsive Small Molecule Inhibitors for the Remote Control of Enzyme Activity. Laczi D, Johnstone MD, Fleming CL. Chem Asian J 17 e202200200 (2022)

Articles citing this publication (7)

  1. Characterizing the Hot Spots Involved in RON-MSPβ Complex Formation Using In Silico Alanine Scanning Mutagenesis and Molecular Dynamics Simulation. Zarei O, Hamzeh-Mivehroud M, Benvenuti S, Ustun-Alkan F, Dastmalchi S. Adv Pharm Bull 7 141-150 (2017)
  2. A Selective Biligand Inhibitor of CK2 Increases Caspase-3 Activity in Cancer Cells and Inhibits Platelet Aggregation. Rahnel H, Viht K, Lavogina D, Mazina O, Haljasorg T, Enkvist E, Uri A. ChemMedChem 12 1723-1736 (2017)
  3. A Stapled Peptide Mimic of the Pseudosubstrate Inhibitor PKI Inhibits Protein Kinase A. Manschwetus JT, Bendzunas GN, Limaye AJ, Knape MJ, Herberg FW, Kennedy EJ. Molecules 24 (2019)
  4. Binding assay for characterization of protein kinase inhibitors possessing sub-picomolar to sub-millimolar affinity. Sinijarv H, Wu S, Ivan T, Laasfeld T, Viht K, Uri A. Anal. Biochem. 531 67-77 (2017)
  5. Competitive ligands facilitate dissociation of the complex of bifunctional inhibitor and protein kinase. Ivan T, Enkvist E, Sinijarv H, Uri A. Biophys. Chem. 228 17-24 (2017)
  6. Crystal Structure-Guided Design of Bisubstrate Inhibitors and Photoluminescent Probes for Protein Kinases of the PIM Family. Nonga OE, Lavogina D, Enkvist E, Kestav K, Chaikuad A, Dixon-Clarke SE, Bullock AN, Kopanchuk S, Ivan T, Ekambaram R, Viht K, Knapp S, Uri A. Molecules 26 4353 (2021)
  7. Deactivatable Bisubstrate Inhibitors of Protein Kinases. Sõrmus T, Lavogina D, Enkvist E, Uri A, Viht K. Molecules 27 6689 (2022)


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