Publication

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

Kunig, V. B. K., Potowski, M., Akbarzadeh, M., Klika Škopić, M., Dos Santos Smith, D., Arendt, L., Dormuth, I., Adihou, H., Andlovic, B., Karatas, H., Shaabani, S., Zarganes-Tzitzikas, T., Neochoritis, C. G., Zhang, R., Groves, M., Guéret, S. M., Ottmann, C., Rahnenführer, J., Fried, R., Dömling, A. & Brunschweiger, A., 14-Jun-2020, In : Angewandte Chemie (International ed. in English). 46, p. 20338-20342 6 p.

Research output: Contribution to journalArticleAcademicpeer-review

Copy link to clipboard

Documents

  • TEAD-YAP interaction inhibitors and MDM2 binders from DNA- encoded indole-focused Ugi-peptidomimetics

    Proof, 1.97 MB, PDF document

    Request copy

DOI

  • Verena B K Kunig
  • Marco Potowski
  • Mohammad Akbarzadeh
  • Mateja Klika Škopić
  • Denise Dos Santos Smith
  • Lukas Arendt
  • Ina Dormuth
  • Hélène Adihou
  • Blaž Andlovic
  • Hacer Karatas
  • Shabnam Shaabani
  • Tryfon Zarganes-Tzitzikas
  • Constantinos G Neochoritis
  • Ran Zhang
  • Matthew Groves
  • Stéphanie M Guéret
  • Christian Ottmann
  • Jörg Rahnenführer
  • Roland Fried
  • Alexander Dömling
  • Andreas Brunschweiger

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 languageEnglish
Pages (from-to)20338-20342
Number of pages6
JournalAngewandte Chemie (International ed. in English)
Issue number46
Publication statusE-pub ahead of print - 14-Jun-2020

    Keywords

  • combinatorial chemistry, DNA-encoded library, peptidomimetics, protein-protein interaction inhibition, Ugi reaction, PROTEIN-PROTEIN INTERACTION, HIPPO PATHWAY, DISCOVERY, DESIGN

ID: 127803326