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

doi:10.1021/acs.bioconjchem.6b00293

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 journal › Article › Research › peer-review

19 Citations (Scopus)

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 (K_D = 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 K_D 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 language	English
Pages (from-to)	1900-1910
Number of pages	11
Journal	Bioconjugate Chemistry
Volume	27
Issue number	8
DOIs	https://doi.org/10.1021/acs.bioconjchem.6b00293
Publication status	Published - 17 Aug 2016
Externally published	Yes

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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.",

author = "Taavi Ivan and Erki Enkvist and Birgit Viira and Manoharan, {Ganesh Babu} and Gerda Raidaru and Alexander Pflug and Alam, {Kazi Asraful} and Manuela Zaccolo and Engh, {Richard Alan} and Asko Uri",

note = "Funding Information: This work was supported by grants from the Estonian Research Council (IUT20-17), the Estonian Ministry of Education and Sciences (SF0180121s08), and the Estonian Science Foundation (8230 and 8419). We thank the British Heart Foundation (PG/10/75/28537 and RG/12/3/29423) on behalf of M.Z. We are grateful for support from Norwegian Research Council Project 183376 (R.A.E., A.P.) and the Norwegian Research Council PhD school BioStruct (R.A.E., K.A.A.) for support. Publisher Copyright: {\textcopyright} 2016 American Chemical Society.",

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doi = "10.1021/acs.bioconjchem.6b00293",

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T1 - Bifunctional Ligands for Inhibition of Tight-Binding Protein-Protein Interactions

AU - Ivan, Taavi

AU - Enkvist, Erki

AU - Viira, Birgit

AU - Manoharan, Ganesh Babu

AU - Raidaru, Gerda

AU - Pflug, Alexander

AU - Alam, Kazi Asraful

AU - Zaccolo, Manuela

AU - Engh, Richard Alan

AU - Uri, Asko

N1 - Funding Information: This work was supported by grants from the Estonian Research Council (IUT20-17), the Estonian Ministry of Education and Sciences (SF0180121s08), and the Estonian Science Foundation (8230 and 8419). We thank the British Heart Foundation (PG/10/75/28537 and RG/12/3/29423) on behalf of M.Z. We are grateful for support from Norwegian Research Council Project 183376 (R.A.E., A.P.) and the Norwegian Research Council PhD school BioStruct (R.A.E., K.A.A.) for support. Publisher Copyright: © 2016 American Chemical Society.

PY - 2016/8/17

Y1 - 2016/8/17

N2 - 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.

AB - 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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ER -

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

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