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From Tethered to Freestanding Stabilizers of 14-3-3 Protein-Protein Interactions through Fragment Linking |
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| Authors: | Emira J. Visser Priyadarshini Jaishankar Eline Sijbesma Marloes A. M. Pennings Edmee M. F. Vandenboorn Xavier Guillory R. Jeffrey Neitz John Morrow Shubhankar Dutta Adam R. Renslo Luc Brunsveld Michelle R. Arkin Christian Ottmann |
| Affiliation: | 1. Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands These authors contributed equally to this work.;2. Department of Pharmaceutical Chemistry and Small Molecule Discovery Centre (SMDC), University of California San Francisco (UCSF), San Francisco, CA, 94143 USA These authors contributed equally to this work.;3. Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands;4. Department of Pharmaceutical Chemistry and Small Molecule Discovery Centre (SMDC), University of California San Francisco (UCSF), San Francisco, CA, 94143 USA |
| Abstract: | Small-molecule stabilization of protein-protein interactions (PPIs) is a promising strategy in chemical biology and drug discovery. However, the systematic discovery of PPI stabilizers remains a largely unmet challenge. Herein we report a fragment-linking approach targeting the interface of 14-3-3 and a peptide derived from the estrogen receptor alpha (ERα) protein. Two classes of fragments—a covalent and a noncovalent fragment—were co-crystallized and subsequently linked, resulting in a noncovalent hybrid molecule in which the original fragment interactions were largely conserved. Supported by 20 crystal structures, this initial hybrid molecule was further optimized, resulting in selective, 25-fold stabilization of the 14-3-3/ERα interaction. The high-resolution structures of both the single fragments, their co-crystal structures and those of the linked fragments document a feasible strategy to develop orthosteric PPI stabilizers by linking to an initial tethered fragment. |
| Keywords: | Drug Discovery Fragment Linking Fragment-Based Drug Discovery Molecular Glues Proteins |