JY-2

JY-2 is a moderately selective and orally active Forkhead transcription factor forkhead box O1 (FoxO1) inhibitor that inhibits FoxO1 transcriptional activity with an IC50 of 22 μM. JY-2 shows moderate inhibition against FoxO3a and FoxO4. JY-2 shows anti-diabetic activity[1].

Signaling Pathways >> Others >> Others

Research Areas >> Metabolic Disease

22 μM (FoxO1 transcriptional activity)[1]

JY-2 (10-100 μM; 24 h) 降低棕榈酸 (PA;HY-N0830) 诱导的 HepG2 和 INS-1 细胞脂毒性[1]。 Real Time qPCR[1] Cell Line: HepG2 and INS-1 cells Concentration: 10, 50 and 100 μM Incubation Time: 24 h Result: Reduced palmitic acid (PA)-induced G6Pase and PEPCK mRNA expression. Inhibited PA-induced lipid accumulation. Reduced PA-induced mRNA expression of ER stress markers (ATF3, CHOP and GRP78). Western Blot Analysis[1] Cell Line: HepG2 cells Concentration: 10, 50 and 100 μM Incubation Time: 4 h; in the presence of PA (500μM) Result: Increased p-FoxO1 levels in the whole cell lysate with a concurrent reduction in nuclear FoxO1 levels.

JY-2 (50-200 mg/kg; oral; 3 times for two days or daily for 4 weeks) 在小鼠中显示抗糖尿病作用[1]。 Pharmacokinetic parameters of JY-2[1] Parameters i.v. (20 mg/kg) p.o. (50 mg/kg) AUCall (ng·h/mL) 5017 ± 1038 12270 ± 2775 AUCinf.obs (ng·h/mL) 5030 ± 1037 12400 ± 2753 Cmax (ng/mL) 10790 ± 3269 6826 ± 2342 Tmax (h) 0.1 ± 0.1 0.8 ± 0.7 T1/2 (h) 0.8 ± 0.2 1.3 ± 0.4 MRTinf.obs (h) 0.7 ± 0.1 2.0 ± 0.1 F (%) 97.8 Animal Model: C57BL/6J mice[1] Dosage: 50, 100, 200 mg/kg Administration: Oral, three times for two days (9:00 AM, 7:00 PM, 9:00 AM on the next day) Result: Improved glucose tolerance. Significantly reduced the expression of G6Pase and PEPCK mRNA in the liver. Enhanced mRNA expression of insulin and PDX-1 in the pancreas. Animal Model: db/db mice and C57BL/6J mice, high fat-diet-induced obese diabetic (DIO) model[1] Dosage: 50, 100 mg/kg Administration: Oral, once daily for 4 weeks Result: Decreased the levels of fasting blood glucose, improved glucose tolerance. The expression of ColIV, a fibrosis marker, was also lowered. Animal Model: C57BL/6J mice[1] Dosage: 20 mg/kg or 50 mg/kg Administration: IV or PO (Pharmacokinetic Analysis) Result: Showed an overall good pharmacokinetic profile.

[1]. Choi HE, et al. Novel FoxO1 inhibitor, JY-2, ameliorates palmitic acid-induced lipotoxicity and gluconeogenesis in a murine model. Eur J Pharmacol. 2021 May 15;899:174011.