General description
A cell-permeable phenylsulfonylbenzimidazole compound that is shown to dock in the ligand-binding pocket of both HNF4α and HNF4γ via in silico structural analyses and antagonizes HNF4α DNA binding activity (by 93% after 10 µM overnight treatment of HepG2 cells), effectively inhibiting HNF4α-dependent cellular activities, including HNF4α mRNA transcription (by 62% in murine insulinoma MIN6 and 84% in human hepatoma HepG2 cultures after 5 h and 48 h 5 µM inhibitor treatment, respectively) and OTC (omithine transcarbamoylase) promoter transcription (by 85% & >95% in human HNF4α-transfected HepG2 & CV-1 cells, respectively; 48 hr 1 µM treatment). HNF4γ inhibition by BI6015 is also reported to indirectly lead to decreased binding of transactivators, E47 & PDX-1, to insulin promoter in T6PNE cells (48 h 5 µM 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 µM), but not primary murine hepatocytes, it does cause hepatic steatosis both in vitro (primary murine hepatocytes; 5 µM 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 µM), but not PPARγ or a panel of 41 receptors/enzymes of human, mouse, and rat origin.
Biochem/physiol Actions
Cell permeable: yes
Primary Target
HNFα & γ
Reversible: yes
Packaging
Packaged under inert gas
Other Notes
Kiselyuk, A., et al. 2012. Chem. Biol.19, 806.
Legal Information
CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany
Disclaimer
Toxicity: Standard Handling (A)
| Quality Segment | 100 |
| assay | ≥99% (HPLC) |
| form | powder |
| manufacturer/tradename | Calbiochem® |
| storage condition | OK to freeze,protect from light |
| color | beige |
| solubility | DMSO: 10 mg/mL |
| shipped in | ambient |
| storage temp. | 2-8°C |
| SMILES string | CC1=NC2=C(N1S(C3=CC([N+]([O-])=O)=CC=C3C)(=O)=O)C=CC=C2 |
| InChI | 1S/C15H13N3O4S/c1-10-7-8-12(18(19)20)9-15(10)23(21,22)17-11(2)16-13-5-3-4-6-14(13)17/h3-9H,1-2H3 |
| InChI key | ILVCPQPMRPHZSG-UHFFFAOYSA-N |
