TEAD–YAP Interaction Inhibitors and MDM2 Binders from DNA‐Encoded Indole‐Focused Ugi Peptidomimetics
Open Access
- 14 June 2020
- journal article
- research article
- Published by Wiley in Angewandte Chemie-International Edition
- Vol. 59 (46), 20338-20342
- https://doi.org/10.1002/anie.202006280
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.Keywords
Funding Information
- Deutsche Forschungsgemeinschaft (BR 5049/3-1)
- European Commission (H2020-MSCA-ITN-2015)
- National Institutes of Health (2R01GM097082-05)
- Hartstichting (ESCAPE-HF, 2018B012)
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