GW 6471

880635-03-0

C35H36F3N3O4

H2O : < 0.1 mg/mL (insoluble); DMSO : 125 mg/mL (201.72 mM; Need ultrasonic)

Cell Cycle/DNA Damage

GW 6471 is a potent PPARalpha antagonist. IC50 & Target: PPARalpha^[1] In Vitro: In a cell-based reporter assay, GW 6471 completely inhibits GW409544-induced activation of PPARalpha with an IC₅₀ of 0.24 uM^[1]. The functional role of PPARalpha is evaluated on renal cell carcinoma (RCC) cell viability by MTT assay. Both Caki-1 (VHL wild type) and 786-O (VHL mutated) cells are incubated separately with a specific PPARalpha agonist, WY14, 643, or a specific PPARalpha antagonist, GW 6471 at concentrations from 12.5 to 100 uM for 72 hours, and cell viability is assessed. While WY14, 643 either has no affect on, or slightly increased, cell viability, GW 6471 significantly and dose-dependently inhibits cell viability (up to approximately 80%) in both cell lines^[2]. In Vivo: To test the antitumor activity of PPARalpha antagonism in vivo, a subcutaneous xenograft mouse model is used. Caki-1 cells are implanted subcutaneously in nude (Nu/Nu) mice. After tumor masses reach ?5 mm in diameter, GW 6471 is administrated intraperitoneally every other day for 4 wk at a dose (20 mg/kg mouse body wt) that is described to be effective in an in vivo dose-response study and confirmed here to be efficacious. There are significant differences in tumor growth between vehicle- and GW 6471-treated animals. No toxicity is observed at the doses of GW 6471 based on weights of the animals, and laboratory values, including kidney and liver function tests, are not adversely affected. To demonstrate on-target effects of GW 6471, c-Myc levels are evaluated in the tumors, which show significant decreases in the GW 6471-treated animals^[3].