9YK2
Crystal structure of TEAD2 with non-covalent aryl ether inhibitor.
This is a non-PDB format compatible entry.
Summary for 9YK2
| Entry DOI | 10.2210/pdb9yk2/pdb |
| Descriptor | Transcriptional enhancer factor TEF-4, (3P)-N-methyl-3-(1-methyl-1H-pyrazol-4-yl)-4-[4-(trifluoromethyl)phenoxy]benzene-1-sulfonamide (3 entities in total) |
| Functional Keywords | hippo pathway, transcription factor, inhibitor, transcription |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 53355.26 |
| Authors | Palte, R.L.,Eddins, M.,Vara, B.A.,Schneider, S.E. (deposition date: 2025-10-06, release date: 2026-02-25, Last modification date: 2026-03-11) |
| Primary citation | Vara, B.A.,Lim, J.,Moure, C.J.,Schneider, S.E.,Yeung, C.S.,Zarate, C.,Achab, A.,Cheng, M.,Kim, R.,Foti, R.S.,Long, B.,Zhang, M.,Mansueto, M.S.,Palte, R.L.,Sondey, C.,Eddins, M.,Eulalia Vela Ramirez, J.,Su, D.,Yan, Q.,Beard, A.,McMinn, S.E.,Nogle, L.,Pietrafitta, M.,Darlak, M.,Smith, D.,DiMauro, E.F.,Barry, E.,Simov, V. Discovery and In Vivo Evaluation of Aryl Ether YAP1/TEAD Inhibitors for the Treatment of Hippo-Driven Malignancies. J.Med.Chem., 69:4303-4316, 2026 Cited by PubMed 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 , a highly potent and selective lead compound with significantly improved cross-species pharmacokinetics and solubility compared to early leads. 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. PubMed: 41678808DOI: 10.1021/acs.jmedchem.5c02997 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.16 Å) |
Structure validation
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