9IXT

Crystal structure of TEAD3 YAP binding domain with compound 2

これはPDB形式変換不可エントリーです。

9IXT の概要

• エントリーDOI: 10.2210/pdb9ixt/pdb
• 分子名称: Transcriptional enhancer factor TEF-5, ~{N}-[(1~{S})-4-azanyl-4-oxidanylidene-1-phenyl-butyl]-5-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1~{H}-isoquinoline-2-carboxamide (3 entities in total)
• 機能のキーワード: transcription factor, tead3, transcription
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 77803.28

構造登録者

Yoo, Y. (登録日: 2024-07-29, 公開日: 2025-04-16)

主引用文献

Kim, J.K.,Kim, J.,Kim, H.,Jin, H.,Yoo, Y.,Fei, X.,Maeng, H.J.,Seo, S.Y.,Han, G.,No, K.T.
Structure-based optimization of TEAD inhibitors: Exploring a novel subpocket near Glu347 for the treatment of NF2-mutant cancer.
Bioorg.Chem., 159:108425-108425, 2025

PubMed Abstract: The Hippo signaling pathway is critical for regulating cell growth, tissue homeostasis, and organ size. Dysregulation of this pathway has been associated with a range of pathologies, especially cancer, through its modulation of downstream effectors-Yes-associated protein (YAP) and the transcriptional coactivator with PDZ-binding motif (TAZ). These proteins bind to transcriptional enhanced associate domain (TEAD) proteins and function as transcription factors in the nucleus, producing oncogenic target genes such as CTGF and CYR61. TEAD proteins require palmitoylation via a covalent bond with cysteine in the central pocket to bind YAP/TAZ. Therefore, competitive inhibition that prevents palmitoylation could serve as an effective anticancer strategy. In this study, we analyzed the crystal structures of the known inhibitor VT-105 bound to TEAD3 to identify new binding spots that were previously unexplored, with the aim of discovering more potent compounds using structure-based drug design. Consequently, we identified a novel hydrogen-bonding site and discovered C-2, which effectively binds to this site, as confirmed by X-ray crystallography. Furthermore, C-2 exhibited stable pharmacokinetic properties and demonstrated impressive efficacy in a mouse xenograft model.

PubMed: 40168885
DOI: 10.1016/j.bioorg.2025.108425

実験手法

X-RAY DIFFRACTION (2.5 Å)