TEAD-YAP Interaction Inhibitors and MDM2 Binders from DNA-Encoded Indole-Focused Ugi Peptidomimetics.
DNA-encoded library
Ugi reaction
combinatorial chemistry
peptidomimetics
protein-protein interaction inhibition
Journal
Angewandte Chemie (International ed. in English)
ISSN: 1521-3773
Titre abrégé: Angew Chem Int Ed Engl
Pays: Germany
ID NLM: 0370543
Informations de publication
Date de publication:
09 11 2020
09 11 2020
Historique:
received:
30
04
2020
revised:
20
05
2020
pubmed:
17
6
2020
medline:
30
3
2021
entrez:
16
6
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32537835
doi: 10.1002/anie.202006280
pmc: PMC7689693
doi:
Substances chimiques
Indoles
0
Peptidomimetics
0
Transcription Factors
0
DNA
9007-49-2
MDM2 protein, human
EC 2.3.2.27
Proto-Oncogene Proteins c-mdm2
EC 2.3.2.27
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
20338-20342Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM097082
Pays : United States
Informations de copyright
© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
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