Abstract
DNA-encoded combinatorial synthesis provides efficient and dense coverage of chemical space around privileged molecular structures. The indole side chain of tryptophan plays a prominent role in key, or “hot spot”, regions of protein–protein interactions. A DNA-encoded combinatorial peptoid library was designed based on the Ugi four-component reaction by employing tryptophan-mimetic indole side chains to probe the surface of target proteins. Several peptoids were synthesized on a chemically stable hexathymidine adapter oligonucleotide “hexT”, encoded by DNA sequences, and substituted by azide-alkyne cycloaddition to yield a library of 8112 molecules. Selection experiments for the tumor-relevant proteins MDM2 and TEAD4 yielded MDM2 binders and a novel class of TEAD-YAP interaction inhibitors that perturbed the expression of a gene under the control of these Hippo pathway effectors.
| Original language | English |
|---|---|
| Pages (from-to) | 20338-20342 |
| Number of pages | 5 |
| Journal | Angewandte Chemie - International Edition |
| Volume | 59 |
| Issue number | 46 |
| Early online date | 14 Jun 2020 |
| DOIs | |
| Publication status | Published - 9 Nov 2020 |
Funding
We acknowledge a Boehringer Ingelheim foundation exploration grant, the DFG (Deutsche Forschungsgemeinschaft) grant No. BR 5049/3‐1, the Mercator Research Center Ruhr (MERCUR) Grant Pr‐2016‐0010, the EFRE‐NRW‐funded Drug Discovery Hub Dortmund (DDHD), funding from the European Union through the TASPPI project (H2020‐MSCA‐ITN‐2015, grant agreement ID 675179), National Institute of Health (NIH) (2R01GM097082‐05), COFUND ALERT (grant agreement No 665250), Hartstichting (ESCAPE‐HF, 2018B012), and KWF Kankerbestrijding grant (grant agreement No 10504). We thank Prof. Dr. Dr. h.c. Herbert Waldmann (Max Planck Institute of Molecular Physiology Dortmund) for generous support. We thank the Max Planck Institute of Molecular Physiology Dortmund Protein Facility (DPF) for the expression and purification of hTEAD4. We thank the Lead Discovery Center GmbH Dortmund for support in the cellular assays. We thank Dorothea Kemmler (CeGAT GmbH) for skillful assistance in next‐generation sequencing experiments. We acknowledge a Boehringer Ingelheim foundation exploration grant, the DFG (Deutsche Forschungsgemeinschaft) grant No. BR 5049/3-1, the Mercator Research Center Ruhr (MERCUR) Grant Pr-2016-0010, the EFRE-NRW-funded Drug Discovery Hub Dortmund (DDHD), funding from the European Union through the TASPPI project (H2020-MSCA-ITN-2015, grant agreement ID 675179), National Institute of Health (NIH) (2R01GM097082-05), COFUND ALERT (grant agreement No 665250), Hartstichting (ESCAPE-HF, 2018B012), and KWF Kankerbestrijding grant (grant agreement No 10504). We thank Prof. Dr. Dr. h.c. Herbert Waldmann (Max Planck Institute of Molecular Physiology Dortmund) for generous support. We thank the Max Planck Institute of Molecular Physiology Dortmund Protein Facility (DPF) for the expression and purification of hTEAD4. We thank the Lead Discovery Center GmbH Dortmund for support in the cellular assays. We thank Dorothea Kemmler (CeGAT GmbH) for skillful assistance in next-generation sequencing experiments.
| Funders | Funder number |
|---|---|
| National Institutes of Health | 2R01GM097082‐05, 665250 |
| European Commission | ID 675179, H2020-MSCA-ITN-2015 |
| Deutsche Forschungsgemeinschaft | BR 5049/3‐1 |
Keywords
- combinatorial chemistry
- DNA-encoded library
- peptidomimetics
- protein–protein interaction inhibition
- Ugi reaction