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TEAD–YAP Interaction Inhibitors and MDM2 Binders from DNA‐Encoded Indole‐Focused Ugi Peptidomimetics
Author(s) -
Kunig Verena B. K.,
Potowski Marco,
Akbarzadeh Mohammad,
Klika Škopić Mateja,
Santos Smith Denise,
Arendt Lukas,
Dormuth Ina,
Adihou Hélène,
Andlovic Blaž,
Karatas Hacer,
Shaabani Shabnam,
ZarganesTzitzikas Tryfon,
Neochoritis Constantinos G.,
Zhang Ran,
Groves Matthew,
Guéret Stéphanie M.,
Ottmann Christian,
Rahnenführer Jörg,
Fried Roland,
Dömling Alexander,
Brunschweiger Andreas
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202006280
Subject(s) - peptoid , peptidomimetic , indole test , chemistry , dna , oligonucleotide , small molecule , computational biology , combinatorial chemistry , stereochemistry , biochemistry , biology , peptide
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.