7t2j
Crystal Structure of TEAD2 in a covalent complex with TED-642
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 PubMedTranscriptional enhanced associate domains (TEADs) are transcription factors that bind to cotranscriptional activators like the yes-associated protein (YAP) or its paralog transcriptional coactivator with a PDZ-binding motif (TAZ). TEAD.YAP/TAZ target genes are involved in tissue and immune homeostasis, organ size control, tumor growth, and metastasis. Here, we report isoindoline and octahydroisoindole small molecules with a cyanamide electrophile that forms a covalent bond with a conserved cysteine in the TEAD palmitate-binding cavity. Time- and concentration-dependent studies against TEAD1-4 yielded second-order rate constants k(inact)/K(I) greater than 100 M(-1) s(-1). Compounds inhibited YAP1 binding to TEADs with submicromolar IC(50) values. Cocrystal structures with TEAD2 enabled structure-activity relationship studies. In mammalian cells, compounds suppressed CTGF mRNA levels and inhibited TEAD1-4 transcriptional activity with submicromolar IC(50) values. Inhibition of TEAD binding to YAP1 in mammalian cells was also observed. Several compounds inhibited the cell viability of sarcoma, hepatocellular carcinoma, glioblastoma, and breast cancer cells with single-digit micromolar IC(50) values. Small-Molecule Cyanamide Pan-TEAD.YAP1 Covalent Antagonists.,Bum-Erdene K, Yeh IJ, Gonzalez-Gutierrez G, Ghozayel MK, Pollok K, Meroueh SO J Med Chem. 2023 Jan 12;66(1):266-284. doi: 10.1021/acs.jmedchem.2c01189. Epub , 2022 Dec 23. PMID:36562717[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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