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

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 employing tryptophan-mimetic indole side chains to probe target protein surface. 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 8,112 molecules. Selection experiments on the tumor-relevant proteins MDM2 and TEAD4 yielded MDM2 binders and a novel class of TEAD-YAP interaction inhibitors that perturbed expression of a gene under the control of these Hippo pathway effectors.