9syn
Crystal structure of TEAD4 in complex with Vgll1-peptide and IAG933
Structural highlights
FunctionTEAD4_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 specifically and non-cooperatively to the Sph and GT-IIC 'enhansons' (5'-GTGGAATGT-3') and activates transcription. Binds to the M-CAT motif.[1] [2] Publication Abstract from PubMedThe interaction of transcriptional enhanced associate domain (TEAD) and transcriptional coactivator yes-associated protein (YAP) mediates oncogenic functions downstream of the Hippo pathway. In this report, we outline our efforts to find a potent inhibitor of this protein-protein interaction with suitable properties for clinical evaluation. We detail the medicinal chemistry program that led to the discovery of IAG933, an inhibitor with a balanced ADME profile, enabling its evaluation as a potential treatment option in clinical settings. Discovery of Clinical Candidate IAG933, a Potent YAP-TEAD PPI Disrupter.,Vogtle M, Sellner H, Chapeau E, Furet P, Salem B, Le Douget M, Bordas V, Groell JM, Le Goff AL, Rouzet C, Wietlisbach T, Zimmermann T, McKenna J, Brocklehurst CE, Chene P, Wartmann M, Scheufler C, Kallen J, de Kanter R, Harlfinger S, Zecri F, Schmelzle T, Soldermann N J Med Chem. 2026 Mar 4. doi: 10.1021/acs.jmedchem.5c03009. PMID:41780024[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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