Discovery of Covalent Inhibitors Targeting the Transcriptional Enhanced Associate Domain Central Pocket

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 mo...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2020-10, Vol.63 (20), p.11972-11989
Main Authors: Karatas, Hacer, Akbarzadeh, Mohammad, Adihou, Hélène, Hahne, Gernot, Pobbati, Ajaybabu V, Yihui Ng, Elizabeth, Guéret, Stéphanie M, Sievers, Sonja, Pahl, Axel, Metz, Malte, Zinken, Sarah, Dötsch, Lara, Nowak, Christine, Thavam, Sasikala, Friese, Alexandra, Kang, CongBao, Hong, Wanjin, Waldmann, Herbert
Format: Article
Language:English
Subjects:
Dose-Response Relationship, Drug
Drug Discovery
Fluorescence
Humans
Models, Molecular
Molecular Structure
Pyrones - chemistry
Pyrones - pharmacology
Small Molecule Libraries - chemistry
Small Molecule Libraries - pharmacology
Structure-Activity Relationship
Sulfhydryl Compounds - chemistry
Sulfhydryl Compounds - pharmacology
Transcription Factors - antagonists & inhibitors
Transcription Factors - genetics
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Summary: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 IC50 values, and reduce TEAD target gene expression. This methodology promises to enable new medicinal chemistry programs aimed at the modulation of TEAD activity.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.0c01275