TG68

TG68 is a novel, liver-selective thyroid hormone receptor beta (THRβ) agonist developed as a prodrug of IS25, a halogen-free THRβ selective compound based on the sobetirome scaffold. The drug exhibits strong selectivity for THRβ over THRα, providing hepato-specificity while minimizing extra-hepatic side effects typical of thyroid hormones, particularly cardiac effects. TG68 has demonstrated efficacy in reducing hepatic steatosis, lowering serum triglycerides and cholesterol, and ameliorating liver injury in preclinical models of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). The mechanism involves activation of THRβ in the liver, leading to increased fatty acid beta-oxidation through upregulation of genes such as Acyl-CoA Oxidase-1 and Carnitine palmitoyltransferase-1, as well as activation of AMPK phosphorylation. Additionally, TG68 has shown anti-tumorigenic effects by inducing differentiation of preneoplastic hepatocytes in models of hepatocarcinogenesis. The drug has been tested at doses of 1.4-9.35 mg/kg in preclinical studies, showing comparable efficacy to resmetirom (MGL-3196) with the added benefit of significantly reducing circulating triglycerides by approximately 30%.