Discovery of a novel, liver-targeted thyroid hormone receptor-β agonist, CS271011, in the treatment of lipid metabolism disorders

IntroductionThyroid hormone receptor beta (THR-beta) 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-beta agonist, and assessed the safety and efficiency of CS271011 compared to MGL-3196 in vitro and in vivo. MethodsWe conducted luciferase reporter gene assays to assess the activation of THR-beta and alpha 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. ResultsCompared with MGL-3196, CS271011 showed higher THR-beta 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. ConclusionsCS271011 is a potent and liver-targeted THR-beta agonist for treating lipid metabolism disorders.

Automated summary

In this study, a novel THR-beta agonist called CS271011 was discovered and its safety and efficiency compared to MGL-3196 were assessed. Results showed that CS271011 exhibited higher THR-beta activation in vitro compared to MGL-3196 and demonstrated favorable pharmacokinetic properties and liver enrichment in a diet-induced obesity mice model. Furthermore, CS271011 improved dyslipidemia and liver steatosis. Overall, CS271011 is a potent and liver-targeted THR-beta agonist for treating lipid metabolism disorders.