Authors: Kunig, Verena B. K.
Potowski, Marco
Akbarzadeh, Mohammad
Škopić, Mateja Klika
Santos Smith, Denise dos
Arendt, Lukas
Dormuth, Ina
Adihou, Hélène
Andlovic, Blaž
Karatas, Hacer
Shaabani, Shabnam
Zarganes-Tzitzikas, Tryfon
Neochoritis, Constantinos G.
Zhang, Ran
Groves, Matthew
Guéret, Stéphanie M.
Ottmann, Christian
Rahnenführer, Jörg
Fried, Roland
Dömling, Alexander
Brunschweiger, Andreas
Title: TEAD-YAP interaction inhibitors and MDM2 binders from DNA-encoded indole-focused Ugi-peptidomimetics
Language (ISO): en
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.
Subject Headings: Combinatorial chemistry
DNA-encoded library
Protein–protein interaction inhibition
Ugi reaction
Issue Date: 2020-06-14
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Appears in Collections:Chemische Biologie

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