Background:

ZSTK474 strongly inhibits the growth of tumor cells by direct inhibition activity of PI3K, which includes all isoforms of class I PI3K with IC50 values of 16 nM, 44 nM, 49 nM, and 4.6 nM for PI3Kα, PI3-Kβ, PI3-Kγ, PI3-Kδ, respectively.[1]
PI3Ks are a family of enzymes, which phosphorylate the 3‘- OH position of the inositol ring of phosphoinositides.PI3Ks are divided into three classes based on the structural features and in vitro lipid substrate specificity. The three class-Ia PI3-ks (p110 α / β / δ ) and the sole class-Ib PI3K (p110 γ ) couple growth factor receptors and G-protein-coupled receptors, respectively, to a wide range of downstream pathways. Signal transduction via the PI3K/Akt pathway is essential for regulating cellular activities, such as proliferation, survival, migration, motility and tumorigenesis, in diverse cell types.[2]
ZSTK474 is a potent ATP-competitive pan class I PI3K inhibitor, which has high selectivity over other classes of PI3K and protein kinases. ZSTK474 also inhibited the bone-resorbing activity of mature osteoclasts. Experiments revealed that 0.1μM of ZSTK474 completely prevented pit formation by osteoclasts. Moreover, the IC50 values for PI3Kα, PI3-Kβ, PI3-Kγ, PI3-Kδ are 16 nM, 44 nM,49 nM, and 4.6 nM, respectively.[1]
Melanoma cells injected BDF 1 mice were orally administrated ZSTK474 daily at 100, 200, or 400 mg/kg of body weight from days 0 to 13. By measuring the volume of tumor, the outcomes showed that ZSTK474 administered orally to mice had strong antitumor activity against human cancer xenografts without toxic effects in vital organs. Akt phosphorylation was decreased in xenograft tumors after oral administration of ZSTK474. [3]
参考文献:
1.Toyama S, Tamura N, Haruta K, et al. Research article Inhibitory effects of ZSTK474, a novel phosphoinositide 3-kinase inhibitor, on osteoclasts and collagen-induced arthritis in mice[J]. 2010.
2.Marone R, Cmiljanovic V, Giese B, et al. Targeting phosphoinositide 3-kinase—moving towards therapy[J]. Biochimica et Biophysica Acta (BBA)-Proteins and Proteomics, 2008, 1784(1): 159-185.
3.Yaguchi S, Fukui Y, Koshimizu I, et al. Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor[J]. Journal of the National Cancer Institute, 2006, 98(8): 545-556.