Modulators of 14-3-3 protein-protein interactions

Loes M. Stevers, Eline Sijbesma, Maurizio Botta, Carol Mackintosh, Tomas Obsil, Isabelle Landrieu, Ylenia Cau, Andrew J. Wilson, Anna Karawajczyk, Jan Eickhoff, Jeremy Davis, Michael Hann, Gavin O'Mahony, Richard G. Doveston, Luc Brunsveld, Christian Ottmann

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Abstract

Direct interactions between proteins are essential for the regulation of their functions in biological pathways. Targeting the complex network of protein-protein interactions (PPIs) has now been widely recognized as an attractive means to therapeutically intervene in disease states. Even though this is a challenging endeavor and PPIs have long been regarded as "undruggable" targets, the last two decades have seen an increasing number of successful examples of PPI modulators, resulting in growing interest in this field. PPI modulation requires novel approaches and the integrated efforts of multiple disciplines to be a fruitful strategy. This perspective focuses on the hub-protein 14-3-3, which has several hundred identified protein interaction partners, and is therefore involved in a wide range of cellular processes and diseases. Here, we aim to provide an integrated overview of the approaches explored for the modulation of 14-3-3 PPIs and review the examples resulting from these efforts in both inhibiting and stabilizing specific 14-3-3 protein complexes by small molecules, peptide mimetics, and natural products.

Original languageEnglish
Pages (from-to)3755-3778
Number of pages24
JournalJournal of Medicinal Chemistry
Volume61
Issue number9
DOIs
Publication statusPublished - 10 May 2018

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14-3-3 Proteins
Proteins
Biological Products

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Stevers, Loes M. ; Sijbesma, Eline ; Botta, Maurizio ; Mackintosh, Carol ; Obsil, Tomas ; Landrieu, Isabelle ; Cau, Ylenia ; Wilson, Andrew J. ; Karawajczyk, Anna ; Eickhoff, Jan ; Davis, Jeremy ; Hann, Michael ; O'Mahony, Gavin ; Doveston, Richard G. ; Brunsveld, Luc ; Ottmann, Christian. / Modulators of 14-3-3 protein-protein interactions. In: Journal of Medicinal Chemistry. 2018 ; Vol. 61, No. 9. pp. 3755-3778.
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abstract = "Direct interactions between proteins are essential for the regulation of their functions in biological pathways. Targeting the complex network of protein-protein interactions (PPIs) has now been widely recognized as an attractive means to therapeutically intervene in disease states. Even though this is a challenging endeavor and PPIs have long been regarded as {"}undruggable{"} targets, the last two decades have seen an increasing number of successful examples of PPI modulators, resulting in growing interest in this field. PPI modulation requires novel approaches and the integrated efforts of multiple disciplines to be a fruitful strategy. This perspective focuses on the hub-protein 14-3-3, which has several hundred identified protein interaction partners, and is therefore involved in a wide range of cellular processes and diseases. Here, we aim to provide an integrated overview of the approaches explored for the modulation of 14-3-3 PPIs and review the examples resulting from these efforts in both inhibiting and stabilizing specific 14-3-3 protein complexes by small molecules, peptide mimetics, and natural products.",
author = "Stevers, {Loes M.} and Eline Sijbesma and Maurizio Botta and Carol Mackintosh and Tomas Obsil and Isabelle Landrieu and Ylenia Cau and Wilson, {Andrew J.} and Anna Karawajczyk and Jan Eickhoff and Jeremy Davis and Michael Hann and Gavin O'Mahony and Doveston, {Richard G.} and Luc Brunsveld and Christian Ottmann",
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Stevers, LM, Sijbesma, E, Botta, M, Mackintosh, C, Obsil, T, Landrieu, I, Cau, Y, Wilson, AJ, Karawajczyk, A, Eickhoff, J, Davis, J, Hann, M, O'Mahony, G, Doveston, RG, Brunsveld, L & Ottmann, C 2018, 'Modulators of 14-3-3 protein-protein interactions', Journal of Medicinal Chemistry, vol. 61, no. 9, pp. 3755-3778. https://doi.org/10.1021/acs.jmedchem.7b00574

Modulators of 14-3-3 protein-protein interactions. / Stevers, Loes M.; Sijbesma, Eline; Botta, Maurizio; Mackintosh, Carol; Obsil, Tomas; Landrieu, Isabelle; Cau, Ylenia; Wilson, Andrew J.; Karawajczyk, Anna; Eickhoff, Jan; Davis, Jeremy; Hann, Michael; O'Mahony, Gavin; Doveston, Richard G.; Brunsveld, Luc; Ottmann, Christian.

In: Journal of Medicinal Chemistry, Vol. 61, No. 9, 10.05.2018, p. 3755-3778.

Research output: Contribution to journalArticleAcademicpeer-review

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AU - Landrieu, Isabelle

AU - Cau, Ylenia

AU - Wilson, Andrew J.

AU - Karawajczyk, Anna

AU - Eickhoff, Jan

AU - Davis, Jeremy

AU - Hann, Michael

AU - O'Mahony, Gavin

AU - Doveston, Richard G.

AU - Brunsveld, Luc

AU - Ottmann, Christian

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Stevers LM, Sijbesma E, Botta M, Mackintosh C, Obsil T, Landrieu I et al. Modulators of 14-3-3 protein-protein interactions. Journal of Medicinal Chemistry. 2018 May 10;61(9):3755-3778. https://doi.org/10.1021/acs.jmedchem.7b00574