Discovery and In Vivo Evaluation of Aryl Ether YAP1/TEAD Inhibitors for the Treatment of Hippo-Driven Malignancies

Targeting the YAP1/TEAD interaction, a critical Hippo pathway signaling complex involved in transcriptional aberrations in cancer, represents a novel approach for treating Hippo-driven malignancies including mesothelioma. Our discovery campaign relied on virtual screening, X-ray crystallography and structure-activity relationship (SAR) studies were carried out to invent a novel aryl ether sulfonamide series with promising inhibitory activity. Leveraging synthetic modularity, we applied high-throughput experimentation for reaction optimization to enable key bond disconnections and SAR elucidation via library synthesis, followed by discrete FEP-guided designs, resulting in improved potency and pharmacokinetic profiles. These efforts identified MRK-A, a highly potent and selective lead compound with significantly improved cross-species pharmacokinetics and solubility compared to early leads. MRK-A demonstrated a robust PKPD relationship via selective, dose-dependent modulation of TEAD-driven genes and achieved complete tumor growth inhibition in the mesothelioma NCI-H226 xenograft mouse model with no observed adverse events.