7CNL

Crystal structure of TEAD3 in complex with VT105

7CNL の概要

• エントリーDOI: 10.2210/pdb7cnl/pdb
• 分子名称: Transcriptional enhancer factor TEF-5, N-oxidanyltetradecanamide, PHOSPHATE ION, ... (7 entities in total)
• 機能のキーワード: tead, inhibitor, palmitoylation, hippo pathway, dna binding protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 103816.69

構造登録者

Tang, T.T.,Konradi, A.W. (登録日: 2020-08-01, 公開日: 2021-04-28, 最終更新日: 2023-11-29)

主引用文献

Tang, T.T.,Konradi, A.W.,Feng, Y.,Peng, X.,Ma, M.,Li, J.,Yu, F.X.,Guan, K.L.,Post, L.
Small Molecule Inhibitors of TEAD Auto-palmitoylation Selectively Inhibit Proliferation and Tumor Growth of NF2 -deficient Mesothelioma.
Mol.Cancer Ther., 20:986-998, 2021

PubMed Abstract: Mutations in the neurofibromatosis type 2 () gene that limit or abrogate expression of functional Merlin are common in malignant mesothelioma. Merlin activates the Hippo pathway to suppress nuclear translocation of YAP and TAZ, the major effectors of the pathway that associate with the TEAD transcription factors in the nucleus and promote expression of genes involved in cell proliferation and survival. In this article, we describe the discovery of compounds that selectively inhibit YAP/TAZ-TEAD promoted gene transcription, block TEAD auto-palmitoylation, and disrupt interaction between YAP/TAZ and TEAD. Optimization led to potent analogs with excellent oral bioavailability and pharmacokinetics that selectively inhibit -deficient mesothelioma cell proliferation and growth of subcutaneous tumor xenografts These highly potent and selective TEAD inhibitors provide a way to target the Hippo-YAP pathway, which thus far has been undruggable and is dysregulated frequently in malignant mesothelioma and in other YAP-driven cancers and diseases.

PubMed: 33850002
DOI: 10.1158/1535-7163.MCT-20-0717

実験手法

X-RAY DIFFRACTION (2.6 Å)