TLC-2716 is an orally available, gut- and liver-restricted inhibitor against LXRα and LXRβ, with EC 50 values of 7 nM and 15 nM, respectively. TLC-2716 represses LXRα/β transcriptional activity, downregulates genes involved in lipogenesis, lipid absorption and lipoprotein metabolism, and preserves peripheral reverse cholesterol transport. TLC-2716 reduces lipid accumulation, suppresses inflammation and fibrotic gene expression, enhances triglyceride-rich lipoprotein clearance, and improves glucose homeostasis and insulin sensitivity. TLC-2716 lowers serum and hepatic triglycerides, plasma cholesterol and other atherogenic lipid profiles in experimental models and humanized liver mice. TLC-2716 can be used for the research of dyslipidemia and related cardiometabolic disorders [1].
In Vivo, TLC-2716 (0.3-1 mg/kg; oral gavage; once daily; 3 weeks) dose-dependently improves dyslipidemia in high-fat diet-induced obese mice by reducing hepatic de novo lipogenesis, liver TG content, and plasma TG and TC levels without impairing peripheral reverse cholesterol transport[1]. TLC-2716 (0.1-15 mg/kg; p.o.; daily) reduces dyslipidemia-related endpoints and improves glucose homeostasis in ZDF rats without impairing liver function[1]. TLC-2716 (0.1-1 mg/kg; p.o.; daily; 21 days) reduces hepatic DNL gene expression, liver TG, and plasma TG and TC in high-fat diet-fed SD rats without impairing liver function[1]. TLC-2716 (1 mg/kg; p.o.; daily; 8 days) reduces hepatic expression of lipid metabolism genes and trends to reduce liver TG in human liver chimeric mice[1]. TLC-2716 (15-120 mg/kg; oral gavage; once daily; 26 weeks) reduces plasma TG and TC in lean CD-1 mice without causing observable adverse effects[1]. TLC-2716 (1-15 mg/kg; oral gavage; once daily; 28 days) reduces plasma TG and TC in cynomolgus monkeys without causing observable adverse effects[1].
In Vitro, TLC-2716 (1 h at 4 °C) binds to recombinant human LXRα (EC50 = 7 nM) and LXRβ (EC50 = 15 nM) in a biochemical binding assay[1]. TLC-2716 (16 h) induces NCOR recruitment to LXRα and LXRβ with EC50 values of 8 nM and 11 nM in HEK293 mammalian two‑hybrid assays, and inhibits ABCA1 and SREBP1c reporter activities with IC50 values of 15 nM and 7 nM in HT‑29 and HepG2 cells, respectively[1]. TLC-2716 (5 days) dose-dependently reduces intracellular triglyceride accumulation in primary human Upcyte hepatocytes with an EC50 of 289 nM[1]. In steatotic human liver organoids, TLC-2716 (500 nM-5 μM; 3 days) dose-dependently reduces intracellular lipid content and suppresses expression of LXR-associated, lipid metabolism, inflammation, and fibrosis-related genes, with enhanced effects in GCKRTT organoids[1].
References:
[1]. Li X, et al. An oral, liver-restricted LXR inverse agonist for dyslipidemia: preclinical development and phase 1 trial. Nat Med. 2026;32(3):883-893.
In Vivo, TLC-2716 (0.3-1 mg/kg; oral gavage; once daily; 3 weeks) dose-dependently improves dyslipidemia in high-fat diet-induced obese mice by reducing hepatic de novo lipogenesis, liver TG content, and plasma TG and TC levels without impairing peripheral reverse cholesterol transport[1]. TLC-2716 (0.1-15 mg/kg; p.o.; daily) reduces dyslipidemia-related endpoints and improves glucose homeostasis in ZDF rats without impairing liver function[1]. TLC-2716 (0.1-1 mg/kg; p.o.; daily; 21 days) reduces hepatic DNL gene expression, liver TG, and plasma TG and TC in high-fat diet-fed SD rats without impairing liver function[1]. TLC-2716 (1 mg/kg; p.o.; daily; 8 days) reduces hepatic expression of lipid metabolism genes and trends to reduce liver TG in human liver chimeric mice[1]. TLC-2716 (15-120 mg/kg; oral gavage; once daily; 26 weeks) reduces plasma TG and TC in lean CD-1 mice without causing observable adverse effects[1]. TLC-2716 (1-15 mg/kg; oral gavage; once daily; 28 days) reduces plasma TG and TC in cynomolgus monkeys without causing observable adverse effects[1].
In Vitro, TLC-2716 (1 h at 4 °C) binds to recombinant human LXRα (EC50 = 7 nM) and LXRβ (EC50 = 15 nM) in a biochemical binding assay[1]. TLC-2716 (16 h) induces NCOR recruitment to LXRα and LXRβ with EC50 values of 8 nM and 11 nM in HEK293 mammalian two‑hybrid assays, and inhibits ABCA1 and SREBP1c reporter activities with IC50 values of 15 nM and 7 nM in HT‑29 and HepG2 cells, respectively[1]. TLC-2716 (5 days) dose-dependently reduces intracellular triglyceride accumulation in primary human Upcyte hepatocytes with an EC50 of 289 nM[1]. In steatotic human liver organoids, TLC-2716 (500 nM-5 μM; 3 days) dose-dependently reduces intracellular lipid content and suppresses expression of LXR-associated, lipid metabolism, inflammation, and fibrosis-related genes, with enhanced effects in GCKRTT organoids[1].
References:
[1]. Li X, et al. An oral, liver-restricted LXR inverse agonist for dyslipidemia: preclinical development and phase 1 trial. Nat Med. 2026;32(3):883-893.