Discovery of a novel, liver-targeted thyroid hormone receptor-β agonist, CS271011, in the treatment of lipid metabolism disorders
Suwen Lin, Shengjian Huang, Zhou Deng, Yu Zhang, Lin Huang, Yanyi Wu, Shuyan Lv, Zhiyi Wang, Ning Huang, Lan Wang, Ziqi Chen, Guangyin Yu, Weihua Yin, You Zhou, Zhengyu Fang
Abstract
Introduction Thyroid hormone receptor β (THR-β) plays a critical role in metabolism regulation and has become an attractive target for treating lipid metabolism disorders in recent years. Thus, in this study, we discovered CS271011, a novel THR-β agonist, and assessed the safety and efficiency of CS271011 compared to MGL-3196 in vitro and in vivo . Methods We conducted luciferase reporter gene assays to assess the activation of THR-β and α in vitro. C57BL/6J mice were fed a high-fat diet for 12 weeks, CS271011 was administered by gavage at the dose of 1 mg/kg and 3 mg/kg, and MGL-3196 was administered at the dose of 3 mg/kg for 10 weeks. Body weight, food intake, serum and hepatic parameters, histological analysis, pharmacokinetic studies, RNA sequencing of the liver and heart, and expression of hepatic lipid-metabolic genes were determined to evaluate the safety and efficiency of CS271011. Results Compared with MGL-3196, CS271011 showed higher THR-β activation in vitro. In the diet-induced obesity mice model, CS271011 demonstrated favourable pharmacokinetic properties in mice and was enriched in the liver. Finally, CS271011 improved dyslipidaemia and reduced liver steatosis in the diet-induced obesity murine model. Mechanistically, CS271011 and MGL-3196 showed potent regulation of lipid metabolism-related genes. Conclusions CS271011 is a potent and liver-targeted THR-β agonist for treating lipid metabolism disorders.