7T2M

Crystal Structure of TEAD2 in a covalent complex with TED-664

7T2M の概要

• エントリーDOI: 10.2210/pdb7t2m/pdb
• 分子名称: Transcriptional enhancer factor TEF-4, (3aR,4R,7aS)-4-[2-(trifluoromethyl)anilino]octahydro-2H-isoindole-2-carbonitrile (2 entities in total)
• 機能のキーワード: tead, inhibitor, complex, covalent, allosteric, transcriptional enhancer factor tef-4, transcription
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 53563.67

構造登録者

Bum-Erdene, K.,Gonzalez-Gutierrez, G.,Meroueh, S.O. (登録日: 2021-12-05, 公開日: 2023-06-14, 最終更新日: 2024-10-23)

主引用文献

Bum-Erdene, K.,Yeh, I.J.,Gonzalez-Gutierrez, G.,Ghozayel, M.K.,Pollok, K.,Meroueh, S.O.
Small-Molecule Cyanamide Pan-TEAD·YAP1 Covalent Antagonists.
J.Med.Chem., 66:266-284, 2023

PubMed Abstract: Transcriptional 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 / greater than 100 M s. Compounds inhibited YAP1 binding to TEADs with submicromolar IC 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 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 values.

PubMed: 36562717
DOI: 10.1021/acs.jmedchem.2c01189

実験手法

X-RAY DIFFRACTION (2.81 Å)