Discovery of Covalent Inhibitors Targeting the Transcriptional Enhanced Associate Domain Central Pocket.
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
22 10 2020
22 10 2020
Historique:
pubmed:
11
9
2020
medline:
19
12
2020
entrez:
10
9
2020
Statut:
ppublish
Résumé
Transcriptional enhanced associate domain (TEAD) transcription factors together with coactivators and corepressors modulate the expression of genes that regulate fundamental processes, such as organogenesis and cell growth, and elevated TEAD activity is associated with tumorigenesis. Hence, novel modulators of TEAD and methods for their identification are in high demand. We describe the development of a new "thiol conjugation assay" for identification of novel small molecules that bind to the TEAD central pocket. The assay monitors prevention of covalent binding of a fluorescence turn-on probe to a cysteine in the central pocket by small molecules. Screening of a collection of compounds revealed kojic acid analogues as TEAD inhibitors, which covalently target the cysteine in the central pocket, block the interaction with coactivator yes-associated protein with nanomolar apparent IC
Identifiants
pubmed: 32907324
doi: 10.1021/acs.jmedchem.0c01275
pmc: PMC7586386
doi:
Substances chimiques
Pyrones
0
Small Molecule Libraries
0
Sulfhydryl Compounds
0
Transcription Factors
0
kojic acid
6K23F1TT52
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
11972-11989Références
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