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 language | English |
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Article number | e202300636 |
Number of pages | 9 |
Journal | ChemBioChem |
Volume | 25 |
Issue number | 1 |
DOIs | |
Publication status | Published - 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
Funders | Funder number |
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Marie Skłodowska‐Curie | 754462, 675179 |
European Commission | |
H2020 European Research Council | 101098234 |
Nederlandse Organisatie voor Wetenschappelijk Onderzoek | |
China Scholarship Council | CSC 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