TEAD-YAP Interaction Inhibitors and MDM2 Binders from DNA-Encoded Indole-Focused Ugi PeptidomimeticsKunig, 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 journal › Article › Academic › peer-review
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.
|Number of pages||6|
|Journal||Angewandte Chemie (International ed. in English)|
|Publication status||E-pub ahead of print - 14-Jun-2020|
- combinatorial chemistry, DNA-encoded library, peptidomimetics, protein-protein interaction inhibition, Ugi reaction, PROTEIN-PROTEIN INTERACTION, HIPPO PATHWAY, DISCOVERY, DESIGN