PIK-75

PIK-75 is a potent, isoform-selective p110α inhibitor with IC50 of 0.3 nM, displays >100-fold selectivity over p110β, p110δ and PI3K C2b; blocks the phosphorylation of PKB induced by insulin on both Ser473 and Thr308 in CHO-IR cell (IC50=78 nM), inhibits PI3K activation associated with dramatic suppression of downstream signaling events, including AKT phosphorylation, IKK activation, and NF-kappaB transcription; potently and dose dependently inhibits in vitro and in vivo production of TNF-alpha and IL-6, diminishes the induced expression of human endothelial cell adhesion molecules (E-selectin, ICAM-1, and VCAM-1), and blocks human monocyte-endothelial cell adhesion; exhibits significant anti-tumor effectiveness in vivo. (In Vitro) :PIK-75 also inhibits p110δ, PI3KC2β, mTORC1, ATM, hsVPS34, PI3KC2α, mTORC2, ATR and PI4KIIIβ with IC50s of 510 nM, ~1 μM, ~1 μM, 2.3 μM, 2.6 μM, ~10 μM, ~10 μM, 21 μM, ~50 μM, respectively.PIK-75 alone blocks Thr 308 phosphorylation in L6 myotubes and 3T3-L1 adipocytes with IC50 values of 1.2 and 1.3 μM, respectively.PIK-75 (1-1000 nM; 5 min) blocks the phosphorylation of PKB induced by insulin on both Ser473and Thr308 in CHO-IR cells in a dose-dependent manner, with an IC50 of 78 nM.PIK-75 (0.1-1000 nM; 48 hours) inhibits the proliferation and survival of pancreatic cancer cells through apoptotic cell death.PIK-75 (0.1-1000 nM) also reduces the colony formation of pancreatic cancer MIA PaCa-2 and AsPC-1 cells. (In Vivo) :PIK-75 (2 mg/kg) potentiates anticancer activity of Gemcitabine (20 mg/kg) in vivo. Gemcitabine (20 mg/kg) or PIK-75 (2 mg/kg) alone reduces the tumor growth to similar degree. Beneficial effect of PIK-75/Gemcitabine is evident as this combination markedly reduces the tumor growth in vivowithout affecting the body weights of mice.