Phosphatidylinositol 3-kinase (PI3K) signaling through Akt/PKB and the mammalian target of rapamycin (mTOR) controls gene expression related to cell proliferation, differentiation, and apoptosis. Increased activity of this pathway is important in many types of cancer. VS-5584 is a purine analog that inhibits mTOR (IC50 = 37 nM) and PI3K (IC50s = 16, 68, 25, and 42 nM for the α, β, γ, and δ isoforms, respectively) without relevant activity against more than 400 additional lipid and protein kinases. By inhibiting the phosphorylation of substrates downstream of PI3K and mTOR, VS-5584 demonstrates broad anti-proliferative sensitivity leading to tumor growth inhibition in human tumor models.
