Identification of 4-aminopyrazolopyrimidine metabolite that may contribute to the hypolipidemic effects of LY2584702 in Long Evans diet induced obese rats

LY2584702 is an inhibitor of p70 S6 kinase-1 previously developed for the treatment of cancer. In two phase 1 trials in oncology patients, significant reductions of total cholesterol, low density lipoprotein cholesterol (LDL-C) and triglyceride was observed. In the current study, we sought to understand the potential mechanism of action of this compound in regulation of lipid metabolism. In Long Evans diet induced obese (DIO) rats, oral administration of LY2584702 for 3 to 4 weeks led to robust reduction of LDL-C up to 60%. An unexpected finding of liver triglyceride (TG) increase implicated a metabolite of LY2584702, 4-aminopyrazolo[3,4-d]pyrimidine (4-APP) in modulation of lipid metabolism in these rats. We showed that low dose 4-APP, when administered orally for 3 to 4 weeks to Long Evans DIO rats, produced lipoprotein profile changes that were strikingly similar to LY2584702. Kinetic studies suggested that both LY2584702 and 4-APP had no effect on chylomicron-TG secretion and only exerted a modest effect on hepatic VLDL-TG secretion. In human hepatoma HepG2 cells 4-APP, but not LY2584702, increased LDL uptake. We hypothesize that generation of the 4-APP metabolite may contribute to the efficacy of LY2584702 in LDL-C lowering in rats and potentially in humans as well. This mechanism of LDL-C lowering may include inhibition of VLDL production and increase in LDL clearance.