9yk2
Crystal structure of TEAD2 with non-covalent aryl ether inhibitor.
Structural highlights
FunctionTEAD2_HUMAN Transcription factor which plays a key role in the Hippo signaling pathway, a pathway involved in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein MST1/MST2, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Acts by mediating gene expression of YAP1 and WWTR1/TAZ, thereby regulating cell proliferation, migration and epithelial mesenchymal transition (EMT) induction. Binds to the SPH and GT-IIC 'enhansons' (5'-GTGGAATGT-3'). May be involved in the gene regulation of neural development. Binds to the M-CAT motif.[1] [2] Publication Abstract from PubMedTargeting 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. Discovery and In Vivo Evaluation of Aryl Ether YAP1/TEAD Inhibitors for the Treatment of Hippo-Driven Malignancies.,Vara BA, Lim J, Moure CJ, Schneider SE, Yeung CS, Zarate C, Achab A, Cheng M, Kim R, Foti RS, Long B, Zhang M, Mansueto MS, Palte RL, Sondey C, Eddins M, Eulalia Vela Ramirez J, Su D, Yan Q, Beard A, McMinn SE, Nogle L, Pietrafitta M, Darlak M, Smith D, DiMauro EF, Barry E, Simov V J Med Chem. 2026 Feb 12. doi: 10.1021/acs.jmedchem.5c02997. PMID:41678808[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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