TEAD-YAP Interaction Inhibitors and MDM2 Binders from DNA-Encoded Indole-Focused Ugi Peptidomimetics

Angew Chem Int Ed Engl. 2020 Nov 9;59(46):20338-20342. doi: 10.1002/anie.202006280. Epub 2020 Jul 15.


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: DNA-encoded library; Ugi reaction; combinatorial chemistry; peptidomimetics; protein-protein interaction inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA / metabolism*
  • Humans
  • Indoles / metabolism*
  • Peptidomimetics*
  • Protein Binding
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • Transcription Factors / metabolism*


  • Indoles
  • Peptidomimetics
  • Transcription Factors
  • DNA
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2