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 <b>MRK-A</b>, a highly potent and selective lead compound with significantly improved cross-species pharmacokinetics and solubility compared to early leads. <b>MRK-A</b> 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.
Authors
- R.L. Palte (ORCID: https://orcid.org/0000-0001-6146-0551)
- Michael J. Eddins (ORCID: https://orcid.org/0009-0006-1371-1997)
- Sebastian E. Schneider (ORCID: https://orcid.org/0000-0003-1233-8984)
- Erin F. DiMauro (ORCID: https://orcid.org/0009-0009-5054-1140)
- Casey J. Moure (ORCID: https://orcid.org/0000-0001-5094-2213)
- Brandon Vara (ORCID: https://orcid.org/0000-0002-5029-4911)
- Julie Lim
- Abdelghani Achab
- Spencer E. McMinn (ORCID: https://orcid.org/0009-0007-6633-4870)
- Brian J. Long (ORCID: https://orcid.org/0000-0002-8202-8589)
- Christopher Sondey (ORCID: https://orcid.org/0000-0003-4855-8524)
- Minjia Zhang (ORCID: https://orcid.org/0009-0005-1476-783X)
- Charles S. Yeung (ORCID: https://orcid.org/0000-0001-7320-7190)
- Vladimir Simov (ORCID: https://orcid.org/0000-0002-6068-1894)
- Mangeng Cheng (ORCID: https://orcid.org/0009-0004-4508-3505)
- Ronald M. Kim
- Cayetana Zárate (ORCID: https://orcid.org/0000-0002-4002-6147)
- Adam Beard (ORCID: https://orcid.org/0000-0002-5078-7900)
- My Sam Mansueto (ORCID: https://orcid.org/0000-0001-8633-2556)
- R. Foti (ORCID: https://orcid.org/0009-0006-4744-9958)
- Miroslawa Darlak
- Lisa Nogle
- Mark J. Pietrafitta
- Evan R. Barry (ORCID: https://orcid.org/0009-0001-7720-1893)
- Julia Eulalia Vela Ramirez (ORCID: https://orcid.org/0009-0008-4078-3050)
- D.P. Smith
- Qingynu Yan
- Dan Su
Institutions
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-02-12
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c02997
- Primary Topic
- Hippo pathway signaling and YAP/TAZ
- Type
- article
- Field-Weighted Citation Impact
- 0.00