7WMO

A novel chemical derivative(92) of THRB agonist

7WMO の概要

• エントリーDOI: 10.2210/pdb7wmo/pdb
• 分子名称: Isoform Beta-2 of Thyroid hormone receptor beta, Nuclear receptor coactivator 2, 2-[[1-ethoxy-7-[4-(3-fluoranyl-5-methoxy-phenyl)carbonyl-2,6-dimethyl-phenoxy]-4-oxidanyl-isoquinolin-3-yl]carbonylamino]ethanoic acid, ... (4 entities in total)
• 機能のキーワード: transcription factor, ligand, transcription
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 31323.11

構造登録者

Yao, B.Q.,Li, Y. (登録日: 2022-01-15, 公開日: 2022-05-18, 最終更新日: 2023-11-29)

主引用文献

Li, Q.,Yao, B.,Zhao, S.,Lu, Z.,Zhang, Y.,Xiang, Q.,Wu, X.,Yu, H.,Zhang, C.,Li, J.,Zhuang, X.,Wu, D.,Li, Y.,Xu, Y.
Discovery of a Highly Selective and H435R-Sensitive Thyroid Hormone Receptor beta Agonist.
J.Med.Chem., 65:7193-7211, 2022

PubMed Abstract: The design and development of agonists selectively targeting thyroid hormone receptor β (TRβ) and TRβ mutants remain challenging tasks. In this study, we first adopted the strategy of breaking the "His-Phe switch" to solve two problems, simultaneously. A structure-based design approach was successfully utilized to obtain compound , which is a potent TRβ agonist (EC: 21.0 nM, 85.0% of the maximum efficacy of ) with outstanding selectivity for TRβ over TRα and also effectively activates the TRβ mutant. Then, we developed a highly efficient synthetic method for . Our serials of cocrystal structures revealed detailed structural mechanisms in overcoming subtype selectivity and rescuing the H435R mutation. also showed excellent lipid metabolism, safety, metabolic stability, and pharmacokinetic properties. Collectively, is a well-characterized selective and mutation-sensitive TRβ agonist for further investigating its function in treating dyslipidemia, nonalcoholic steatohepatitis (NASH), and resistance to thyroid hormone (RTH).

PubMed: 35507418
DOI: 10.1021/acs.jmedchem.2c00144

実験手法

X-RAY DIFFRACTION (2.56 Å)