8caa | pdb_00008caa

Crystal structure of TEAD4 in complex with YTP-13

spinqualitylabelsall models 8caa, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8caa is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: PO4, U3F, U3O Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function TEAD4_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. Publication Abstract from PubMed The inhibition of the YAP-TEAD protein-protein interaction constitutes a promising therapeutic approach for the treatment of cancers linked to the dysregulation of the Hippo signaling pathway. The identification of a class of small molecules which potently inhibit the YAP-TEAD interaction by binding tightly to the Omega-loop pocket of TEAD has previously been communicated. This report details the further multi-parameter optimization of this class of compounds resulting in advanced analogs combining nanomolar cellular potency with a balanced ADME and off-target profile, and efficacy of these compounds in tumor bearing mice is demonstrated for the first time. Optimization of a Class of Dihydrobenzofurane Analogs Toward Orally Efficacious YAP-TEAD Protein-Protein Interaction Inhibitors.,Sellner H, Chapeau E, Furet P, Voegtle M, Salem B, Le Douget M, Bordas V, Groell JM, Le Goff AL, Rouzet C, Wietlisbach T, Zimmermann T, McKenna J, Brocklehurst C, Chene P, Wartmann M, Scheufler C, Kallen J, Williams G, Harlfinger S, Traebert M, Dumotier B, Schmelzle T, Soldermann N ChemMedChem. 2023 Mar 29:e202300051. doi: 10.1002/cmdc.202300051. PMID:36988034 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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