Hacer Karatas; Mohammad Akbarzadeh; Hélène Adihou; Gernot Hahne; Ajaybabu V. Pobbati; Elizabeth Yihui Ng; Stéphanie M. Guéret; Sonja Sievers; Axel Pahl; Malte Metz; Sarah Zinken; Lara Dötsch; Christine Nowak; Sasikala Thavam; Alexandra Friese; Congbao Kang; Wanjin Hong; Herbert Waldmann
J. Med. Chem., 2020, 63(20), 11972-11989
https://doi.org/10.1021/acs.jmedchem.0c01275

Abstract

Transcriptional enhanced associate domain (TEAD) transcription factors together with coactivators and corepressors modulate the expression of genes that regulate fundamental processes, 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 analogs as TEAD inhibitors, which covalently targets the cysteine in the central pocket, blocks the interaction with coactivator Yes-Associated Protein (YAP) with nanomolar apparent IC50 values and reduces TEAD target gene expression. This methodology promises to enable new medicinal chemistry programs aimed at the modulation of TEAD activity.