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

  • J Med Chem. 2026 Feb 26;69(4):4303-4316. doi: 10.1021/acs.jmedchem.5c02997.
Brandon A Vara  1 ,  Jongwon Lim  1 ,  Casey J Moure  1 ,  Sebastian E Schneider  1 ,  Charles S Yeung  1 ,  Cayetana Zarate  1 ,  Abdelghani Achab  1 ,  Mangeng Cheng  1 ,  Ronald Kim  2 ,  Robert S Foti  1 ,  Brian Long  1 ,  Minjia Zhang  1 ,  My S Mansueto  1 ,  Rachel L Palte  1 ,  Christopher Sondey  1 ,  Michael Eddins  3 ,  Julia Eulalia Vela Ramirez  1 ,  Dan Su  1 ,  Qingynu Yan  1 ,  Adam Beard  1 ,  Spencer E McMinn  1 ,  Lisa Nogle  1 ,  Mark Pietrafitta  1 ,  Miroslawa Darlak  1 ,  David Smith  1 ,  Erin F DiMauro  1 ,  Evan Barry  1 ,  Vladimir Simov  1
Affiliations
  • 1. Merck & Co., Inc., Boston, Massachusetts 02115, United States.
  • 2. Merck & Co., Inc., Rahway, New Jersey 07065, United States.
  • 3. Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
PMID: 41678808 DOI: 10.1021/acs.jmedchem.5c02997
Abstract

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.

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