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论文题目
Discovery of a Highly Selective and H435R Sensitive Thyroid Hormone Receptor β Agonist
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作者
Qiu Li#, Benqiang Yao#, Shiting Zhao, Zhou Lu, Yan Zhang, Qiuping Xiang, Xishan Wu, Haonan Yu, Cheng Zhang, Junhua Li, Xiaoxi Zhuang, Donghai Wu, Yong Li, Yong Xu
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论文出处
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刊物名称
Journal of Medicinal Chemistry
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年卷期页
2022, 65, 10, 7193-7211
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联系作者
Yong Xu
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影响因子
8.039
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摘要
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 16g, which is a potent TRβ agonist (EC50: 21.0 nM, 85.0% of the maximum efficacy of 1) with outstanding selectivity for TRβ over TRα and also effectively activates the TRβH435R mutant. Then, we developed a highly efficient synthetic method for 16g. Our serials of cocrystal structures revealed detailed structural mechanisms in overcoming subtype selectivity and rescuing the H435R mutation. 16g also showed excellent lipid metabolism, safety, metabolic stability, and pharmacokinetic properties. Collectively, 16g 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).
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英文摘要
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外单位作者单位
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备注
