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.