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
Angew. Chem. Int. Ed. Engl., 2020, 59(46), 20338-20342
https://doi.org/10.1002/anie.202006280

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 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.