Back to your search result

Description

A cell-permeable phenylsulfonylbenzimidazole compound that is shown to dock in the ligand-binding pocket of both HNF4&,amp,alpha, and HNF4&,amp,gamma, via in silico structural analyses and antagonizes HNF4&,amp,alpha, DNA binding activity (by 93% after 10 &,amp,micro,M overnight treatment of HepG2 cells), effectively inhibiting HNF4&,amp,alpha,-dependent cellular activities, including HNF4&,amp,alpha, mRNA transcription (by 62% in murine insulinoma MIN6 and 84% in human hepatoma HepG2 cultures after 5 h and 48 h 5 &,amp,micro,M inhibitor treatment, respectively) and OTC (omithine transcarbamoylase) promoter transcription (by 85% &,amp, &,gt,95% in human HNF4&,amp,alpha,-transfected HepG2 &,amp, CV-1 cells, respectively, 48 hr 1 &,amp,micro,M treatment). HNF4&,amp,gamma, inhibition by BI6015 is also reported to indirectly lead to decreased binding of transactivators, E47 &,amp, PDX-1, to insulin promoter in T6PNE cells (48 h 5 &,amp,micro,M treatment). Although BI6015 is found to exhibit cancer-selective cytotoxicity toward a panel of 58 human cancer cells and Hep3B-Luc (Effective conc. 1 to 10 &,amp,micro,M), but not primary murine hepatocytes, it does cause hepatic steatosis both in vitro (primary murine hepatocytes, 5 &,amp,micro,M for 3 days) and in mice in vivo (10 to 30 mg/kg/day for 5 days via i.p.) and is effectively metabolized by liver enzymes, limiting its in vivo efficacy in treating human Hep3B-derived liver tumor in mice. BI6015 also inhibits Human CYP450 2C19 and rat L-type calcium channel (by 94% and 83%, respectively, at 10 &,amp,micro,M), but not PPAR&gamma, or a panel of 41 receptors/enzymes of human, mouse, and rat origin., A cell-permeable phenylsulfonylbenzimidazole that is shown to dock in the ligand-binding pocket of both HNF4&alpha, and HNF4&gamma, and antagonize HNF4&alpha, DNA binding activity in HepG2 cells (by 93%, 10 µ,M overnight), effectively inhibiting HNF4&alpha,-dependent cellular activities (Effective conc. 1 to 5 µ,M). HNF4&gamma, inhibition by BI6015 can also lead to decreased insulin promoter binding by transactivators E47 & PDX-1 in T6PNE cells (5 µ,M 48 h). Although BI6015 is found to exhibit cancer-selective cytotoxicity toward a panel of 58 human cancer cells and Hep3B-Luc (Effective conc. 1 to 10 µ,M), but not primary murine hepatocytes, it does cause hepatic steatosis both in vitro and in mice in vivo, limiting its use in animal studies. BI6015 also inhibits Human CYP450 2C19 and rat L-type calcium channel (by 94% and 83%, respectively, at 10 µ,M), but not PPAR&gamma, or a panel of 41 receptors/enzymes of human, mouse, and rat origin.