TEAD-YAP Interaction Inhibitors and MDM2 Binders from DNA-Encoded Indole-Focused Ugi Peptidomimetics.
Kunig VBK., 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 CG., Zhang R., Groves M., Guéret SM., Ottmann C., Rahnenführer J., Fried R., Dömling A., Brunschweiger A.
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.