Discovery of 14-3-3 PPI Stabilizers by Extension of an Amidine-Substituted Thiophene Fragment

Qi Wu, Federica Centorrino, Xavier Guillory, Madita Wolter, Christian Ottmann (Corresponding author), Peter J Cossar (Corresponding author), Luc Brunsveld (Corresponding author)

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)
75 Downloads (Pure)

Abstract

Protein-protein interaction (PPI) modulation is a promising approach in drug discovery with the potential to expand the 'druggable' proteome and develop new therapeutic strategies. While there have been significant advancements in methodologies for developing PPI inhibitors, there is a relative scarcity of literature describing the 'bottom-up' development of PPI stabilizers (Molecular Glues). The hub protein 14-3-3 and its interactome provide an excellent platform for exploring conceptual approaches to PPI modulation, including evolution of chemical matter for Molecular Glues. In this study, we employed a fragment extension strategy to discover stabilizers for the complex of 14-3-3 protein and an Estrogen Receptor alpha-derived peptide (ERα). A focused library of analogues derived from an amidine-substituted thiophene fragment enhanced the affinity of the 14-3-3/ERα complex up to 6.2-fold. Structure-activity relationship (SAR) analysis underscored the importance of the newly added, aromatic side chain with a certain degree of rigidity. X-ray structural analysis revealed a unique intermolecular π-π stacking binding mode of the most active analogues, resulting in the simultaneous binding of two molecules to the PPI binding pocket. Notably, analogue 11 displayed selective stabilization of the 14-3-3/ERα complex.

Original languageEnglish
Article numbere202300636
Number of pages9
JournalChemBioChem
Volume25
Issue number1
DOIs
Publication statusPublished - 2 Jan 2024

Bibliographical note

© 2023 Wiley-VCH GmbH.

Funding

We thank Joost L. J. van Dongen for HR‐MS measurements. This research was supported by the European Union through ERC Advanced Grant PPI‐Glue (101098234), Initial Training Network TASPPI, funded by the H2020 Marie Curie Actions (Grant Agreement 675179), through a Eurotech Postdoctoral Fellow program (Marie Skłodowska‐Curie Co‐funded, grant number 754462), the Netherlands Organization for Scientific Research via NWO Veni VI.Veni.212.27, and a China Scholarship Council PhD fellowship (CSC 201906050031). Views and opinions expressed are however those of the authors only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible for them

FundersFunder number
Marie Skłodowska‐Curie754462, 675179
European Commission
H2020 European Research Council101098234
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
China Scholarship CouncilCSC 201906050031

    Keywords

    • 14-3-3
    • Erα
    • Fragment
    • Molecular Glue
    • PPI Stabilizer
    • Drug Discovery/methods
    • Estrogen Receptor alpha
    • Protein Binding
    • 14-3-3 Proteins/chemistry
    • Structure-Activity Relationship

    Fingerprint

    Dive into the research topics of 'Discovery of 14-3-3 PPI Stabilizers by Extension of an Amidine-Substituted Thiophene Fragment'. Together they form a unique fingerprint.

    Cite this