Abstract
Protein–protein interactions (PPIs) of 14-3-3 proteins are a model system for studying PPI stabilization. The complex natural product Fusicoccin A stabilizes many 14-3-3 PPIs but is not amenable for use in SAR studies, motivating the search for more drug-like chemical matter. However, drug-like 14-3-3 PPI stabilizers enabling such studies have remained elusive. An X-ray crystal structure of a PPI in complex with an extremely low potency stabilizer uncovered an unexpected non-protein interacting, ligand-chelated Mg2+ leading to the discovery of metal-ion-dependent 14-3-3 PPI stabilization potency. This originates from a novel chelation-controlled bioactive conformation stabilization effect. Metal chelation has been associated with pan-assay interference compounds (PAINS) and frequent hitter behavior, but chelation can evidently also lead to true potency gains and find use as a medicinal chemistry strategy to guide compound optimization. To demonstrate this, we exploited the effect to design the first potent, selective, and drug-like 14-3-3 PPI stabilizers.
| Original language | English |
|---|---|
| Pages (from-to) | 7131-7139 |
| Number of pages | 9 |
| Journal | Chemistry : A European Journal |
| Volume | 26 |
| Issue number | 31 |
| Early online date | 7 Apr 2020 |
| DOIs | |
| Publication status | Published - 2 Jun 2020 |
Funding
The crystallographic data collection was performed at the Deutsches Elektronen‐Synchrotron (DESY, PETRA III) of Hamburg (Germany). The authors acknowledge Anna Jonson and Kristina Öhlén of the Separation Science Group at AstraZeneca Gothenburg for help with chiral HPLC, Richard Lewis of the NMR Group at AstraZeneca Gothenburg for the VCD analysis and the interpretation of the 1D selective ROE NMR spectra, Fredrik Wågberg and Johan Wernevik for assistance with HRMS determination for compounds ( R )‐ 6 and ( R )‐ 9 . Anaïs Noisier is thanked for her support in the peptide synthesis. François‐Xavier Cantrelle is also thanked for NMR data acquisition and technical advice. This work is supported by the Initial Training Network TASPPI, funded by the H2020 Marie Skłodowska‐Curie Actions of the European Commission under Grant Agreement 675179. The NMR facilities at Univ. Lille were funded by the Nord Region Council, CNRS, Institut Pasteur de Lille, the European Community (ERDF), the French Ministry of Research and the University of Lille and by the CTRL CPER co‐funded by the European Union with the European Regional Development Fund (ERDF), by the Hauts de France Regional Council (contract n° 17003781), Métropole Européenne de Lille (contract n° 2016 ESR 05), and French State (contract n° 2017‐R3‐CTRL‐Phase 1). We acknowledge support for the NMR facilities from TGE RMN THC (CNRS, FR‐3050) and FRABio (Univ. Lille, CNRS, FR‐3688).
| Funders | Funder number |
|---|---|
| AstraZeneca | |
| European Union's Horizon 2020 - Research and Innovation Framework Programme | 675179 |
| Marie Skłodowska‐Curie | |
| Université de Lille | |
| European Commission | |
| European Regional Development Fund |
Keywords
- chelates
- drug design
- medicinal chemistry
- PAINS
- protein–protein interaction stabilization