AZ'4331 is a novel pan-TEAD auto-palmitoylation inhibitor for the treatment of Hippo pathway-altered cancers.

TEAD proteins are the transcriptional effectors of the Hippo signaling pathway that bind coactivators YAP/TAZ to activate gene expression programs involved in cell survival, proliferation, and drug resistance. TEAD-dependent transcription is elevated in many tumor types through a variety of mechanisms including loss-of-function mutations in Hippo pathway tumor suppressors, and as an adaptive resistance mechanism in response to EGFR TKI and KRAS inhibition. Therefore, targeting the YAP/TAZ-TEAD signaling axis has the potential to provide clinical benefit either as a monotherapy or combination strategy across diverse indications. Here, we characterize the activity of AZ'4331, a TEAD palmitoylation inhibitor which displays anti-tumor efficacy in multiple pre-clinical models of Hippo pathway-dysregulated cancers. Metabolic labeling studies show that TEAD proteins rapidly cycle between apo- and palmitoylated states, and that AZ'4331 inhibits the palmitoylation of TEAD1-4 paralogs. Functionally, AZ'4331 reduces YAP-TEAD binding and TEAD-dependent transcription, leading to reduced cell cycle progression and proliferation in Hippo pathway-altered NCI-H226 cells in vitro. AZ'4331 elicits robust monotherapy activity across mesothelioma and head and neck squamous cell carcinoma xenografts, and significantly enhances the efficacy of osimertinib in EGFR-mutant non-small cell lung cancer in vitro. However, this combination benefit only translates in vivo when osimertinib is administered at doses below clinically relevant levels, suggesting that TEAD inhibition enhances the efficacy of osimertinib in settings where EGFR signaling is incompletely suppressed. Collectively, these findings highlight the promise of TEAD inhibition as a therapeutic strategy for the treatment of Hippo pathway-driven cancers.