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 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.