TEAD1-selective palmitoylation inhibitor

TEAD1-selective palmitoylation inhibitors are a class of small molecule therapeutics designed to target the Hippo signaling pathway by specifically inhibiting the auto-palmitoylation of TEA Domain Transcription Factor 1 (TEAD1). These compounds, exemplified by the preclinical research compound VT103 developed by Vivace Therapeutics, bind to the highly conserved central palmitate-binding pocket of TEAD1. This binding prevents the attachment of palmitate, which is essential for the structural stability of TEAD and its ability to interact with transcriptional co-activators Yes-associated protein (YAP) and WW domain-containing transcription regulator protein 1 (TAZ). By disrupting the YAP/TAZ-TEAD1 complex, these inhibitors suppress the transcription of genes that drive cell proliferation, survival, and migration in Hippo-dysregulated malignancies, such as NF2-deficient malignant mesothelioma. While designed for isoform selectivity, preclinical evidence suggests that TEAD1-selective inhibitors may still exhibit on-target renal toxicities, such as proteinuric nephropathy, and may demonstrate reduced anti-tumor efficacy compared to pan-TEAD inhibitors when used in combination with other targeted therapies like EGFR or KRAS inhibitors.

Other names

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