7WLX

A novel chemical derivative(53) of THRB agonist

Summary for 7WLX

• Entry DOI: 10.2210/pdb7wlx/pdb
• Descriptor: Isoform Beta-2 of Thyroid hormone receptor beta, Nuclear receptor coactivator 2, 2-[[1-methoxy-4-oxidanyl-7-[4-(phenylmethyl)phenoxy]isoquinolin-3-yl]carbonylamino]ethanoic acid, ... (4 entities in total)
• Functional Keywords: transcription factor, ligand., transcription
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 31219.03

Authors

Yao, B.Q.,Li, Y. (deposition date: 2022-01-14, release date: 2022-05-18, Last modification date: 2024-11-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.39 Å)