Kunig, Verena B. K.Potowski, MarcoAkbarzadeh, MohammadŠkopić, Mateja KlikaSantos Smith, Denise dosArendt, LukasDormuth, InaAdihou, HélèneAndlovic, BlažKaratas, HacerShaabani, ShabnamZarganes-Tzitzikas, TryfonNeochoritis, Constantinos G.Zhang, RanGroves, MatthewGuéret, Stéphanie M.Ottmann, ChristianRahnenführer, JörgFried, RolandDömling, AlexanderBrunschweiger, Andreas2021-07-192021-07-192020-06-14http://hdl.handle.net/2003/4033410.17877/DE290R-22209DNA-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.enAngewandte chemie international edition;Vol. 59. 2020, Issue 46, pp 20338-20342https://creativecommons.org/licenses/by/4.0/Combinatorial chemistryDNA-encoded libraryPeptidomimeticsProtein–protein interaction inhibitionUgi reaction570540article (journal)