TEAD–YAP Interaction Inhibitors and MDM2 Binders from DNA‐Encoded Indole‐Focused Ugi Peptidomimetics

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 w...

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Bibliographic Details
Published in:	Angewandte Chemie International Edition Vol. 59; no. 46; pp. 20338 - 20342
Main Authors:	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, Zarganes‐Tzitzikas, Tryfon, Neochoritis, Constantinos G., Zhang, Ran, Groves, Matthew, Guéret, Stéphanie M., Ottmann, Christian, Rahnenführer, Jörg, Fried, Roland, Dömling, Alexander, Brunschweiger, Andreas
Format:	Journal Article
Language:	English
Published:	WEINHEIM Wiley 09.11.2020 Wiley Subscription Services, Inc John Wiley and Sons Inc
Edition:	International ed. in English
Subjects:	Adapters Alkynes Binders Chains Chemistry Chemistry, Multidisciplinary Combinatorial analysis combinatorial chemistry Communication Communications Cycloaddition Deoxyribonucleic acid DNA DNA - metabolism DNA biosynthesis DNA-encoded library Gene expression Gene sequencing Humans Indoles Indoles - metabolism Inhibitors Libraries MDM2 protein Molecular structure Nucleotide sequence Oligonucleotides Peptidomimetics Physical Sciences Protein Binding Protein interaction Proteins protein–protein interaction inhibition Proto-Oncogene Proteins c-mdm2 - metabolism Science & Technology Transcription Factors - metabolism Tryptophan Ugi reaction Yes-associated protein DNA-encoded library DESIGN Ugi reaction PROTEIN-PROTEIN INTERACTION HIPPO PATHWAY peptidomimetics combinatorial chemistry DISCOVERY protein-protein interaction inhibition
ISSN:	1433-7851, 1521-3773, 1521-3773
Online Access:	Get full text
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Summary:	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. A focused approach: A DNA‐encoded peptoid library was designed by the Ugi multicomponent reaction around indole structures that mimic the side chain of tryptophan. Applying this focused library to the challenging cancer targets MDM2 and hTEAD4 yielded compounds for inhibitor development. Compounds binding to hTEAD4 disrupted the hTEAD4–YAP interaction, and reduced expression of a gene under control of the TEAD–YAP transcription factor complex.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1433-7851 1521-3773 1521-3773
DOI:	10.1002/anie.202006280