TEAD-YAP interaction inhibitors and MDM2 binders from DNA-encoded indole-focused Ugi-peptidomimetics
Loading...
Date
2020-06-14
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
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.
Description
Table of contents
Keywords
Combinatorial chemistry, DNA-encoded library, Peptidomimetics, Protein–protein interaction inhibition, Ugi reaction