Small-Molecule Cyanamide Pan-TEAD·YAP1 Covalent Antagonists

Transcriptional enhanced associate domains (TEADs) are
transcription
factors that bind to cotranscriptional activators like the yes-associated
protein (YAP) or its paralog transcriptional coactivator with a PDZ-binding
motif (TAZ). TEAD·YAP/TAZ target genes are involved in tissue
and immune homeostasis, organ size control, tumor growth, and metastasis.
Here, we report isoindoline and octahydroisoindole small molecules
with a cyanamide electrophile that forms a covalent bond with a conserved
cysteine in the TEAD palmitate-binding cavity. Time- and concentration-dependent
studies against TEAD1-4 yielded second-order rate constants kinact/KI greater
than 100 M–1 s–1. Compounds inhibited
YAP1 binding to TEADs with submicromolar IC50 values. Cocrystal
structures with TEAD2 enabled structure–activity relationship
studies. In mammalian cells, compounds suppressed CTGF mRNA levels
and inhibited TEAD1-4 transcriptional activity with submicromolar
IC50 values. Inhibition of TEAD binding to YAP1 in mammalian
cells was also observed. Several compounds inhibited the cell viability
of sarcoma, hepatocellular carcinoma, glioblastoma, and breast cancer
cells with single-digit micromolar IC50 values.