2. Academic Validation
  3. Discovery of a Highly Selective and H435R-Sensitive Thyroid Hormone Receptor β Agonist

Discovery of a Highly Selective and H435R-Sensitive Thyroid Hormone Receptor β Agonist

  • J Med Chem. 2022 May 26;65(10):7193-7211. doi: 10.1021/acs.jmedchem.2c00144.
Qiu Li 1 2 3,  Benqiang Yao 4,  Shiting Zhao 1 3,  Zhou Lu 4,  Yan Zhang 1 2,  Qiuping Xiang 1 2,  Xishan Wu 1 2,  Haonan Yu 1 2,  Cheng Zhang 1 2,  Junhua Li 1 2,  Xiaoxi Zhuang 1 2,  Donghai Wu 1 5,  Yong Li 4,  Yong Xu 1 5 2
Affiliations

Affiliations

  • 1 Center for Chemical Biology and Drug Discovery, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
  • 2 Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
  • 3 University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing 100049, China.
  • 4 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen 361005, China.
  • 5 China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou 510530, China.
PMID: 35507418 DOI: 10.1021/acs.jmedchem.2c00144
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 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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