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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 publication




Journal article


Angewandte Chemie (International ed. in English)

Publication Date





20338 - 20342


TU Dortmund University, Faculty of Chemistry and Chemical Biology, Otto-Hahn-Strasse 6, 44227, Dortmund, Germany.


Humans, Indoles, Transcription Factors, DNA, Protein Binding, Proto-Oncogene Proteins c-mdm2, Peptidomimetics