Molecular Weight(MW): 417.41
ZSTK474 inhibits class I PI3K isoforms with IC50 of 37 nM in a cell-free assay, mostly PI3Kδ. Phase1/2.
Cited by 9 Publications
5 Customer Reviews
The proliferation of tachyzoites in ARPE-19 cells was examined by fluorescence microscopy. Cells were pre-incubated with PI3K inhibitors, 250 nM GDC-0941 and 10 nM ZSTK474 for 1 h. After washing, the cells were then infected with T. gondii at moi of 5 for 24 h. Cells were fixed and stained with Texas Red?X phalloidin for labeling F-actin (red), and nuclei were stained with DAPI (blue). Data are representative of three independent experiments. Scale bar = 100 uM.
PLoS One 2013 8(6), e66306. ZSTK474 purchased from Selleck.
Effects of Velcade and ZSTK474 on expression of proteins central to the PI3K/Akt pathway in GBM cell lines. U87 and U118 were cultured for 24 h with Velcade (100 nM), ZSTK474 (2.5 uM), or both simultaneously. Lysates were made and subjected to western blot analysis for P-Akt, P-mTOR, P-4EBP1 and cyclin D1 as well as GAPDH loading control.
Int J Oncol 2014 44(2), 557-62. ZSTK474 purchased from Selleck.
Representative Western blot of Erk1/2, phospho-Erk1/2, Akt, phospho-Akt antibodies in BCPAP, K1 and 8505C cells treated at 4 h using IC50 doses. 1, cells untreated; 2, cells treated with RAF265; 3, cells treated with ZSTK474; 4, cells treated with SB590885; 5, cells treated with RAF265+ZSTK474; 6, cells treated with SB590885+ZSTK474.
Invest New Drugs 2014 32(4), 626-35. ZSTK474 purchased from Selleck.
We treated all of drugs in T47D which has a PI3KCA H1044R mutation with the concentration shown below for 1 hour and performed western blot analysis using antibodies to phospho-AKT(SERINE 472), and total AKT.
Saraswati Sukumar of Johns Hopkins University School of Medicine. ZSTK474 purchased from Selleck.
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3. "+" indicates inhibitory effect. Increased inhibition is marked by a higher "+" designation.
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|Description||ZSTK474 inhibits class I PI3K isoforms with IC50 of 37 nM in a cell-free assay, mostly PI3Kδ. Phase1/2.|
|Features||First orally administered PI3K inhibitor used in vivo.|
ZSTK474 at 1 μM potently reduces PI3K activity to 4.7% of the control level, whereas LY2194002 only reduces the activity to 44.6% of the control. ZSTK474 inhibits the activities of recombinant p110β, -γ, and -δ with IC50 of 17 nM, 53 nM, and 6 nM, respectively. ZSTK474 shows potent antiproliferative activity against a panel of 39 human cancer cell lines with mean GI50 of 0.32 μM, more effectively than that of LY294002 or wortmannin with mean GI50 of 7.4 μM or 10 μM, respectively. ZSTK474 treatment at 1 μM blocks membrane ruffling and generation of PIP3 induced by platelet-derived growth factor in murine embryonic fibroblasts (MEFs). ZSTK474 at 10 μM induces apoptosis in OVCAR3 cells, and induces complete G1-phase arrest but not apoptosis in A549 cells. ZSTK474 treatment at 0.5 μM significantly decreases the level of phosphorylated Akt and GSK-3β, as well as the cyclin D1 protein expression. ZSTK474 also inhibits the phosphorylation of other downstream signaling components that are involved in regulating cell proliferation including FKHRL1, FKHR, TSC-2, mTOR, and p70S6K in a dose-dependent manner.  ZSTK474 does not inhibit mTOR at 0.1 μM, and even at a concentration of 100 μM, ZSTK474 inhibits mTOR activity less than 40%.  ZSTK474 blocks VEGF-induced cell migration and the tube formation in human umbilical vein endothelial cells (HUVECs), and inhibits the expression of HIF-1α and secretion of VEGF in RXF-631L cells, exhibiting potent in vitro antiangiogenic activity.  ZSTK474 treatment inhibits the production of IFNγ and IL-17 in concanavalin A-activated T cells, and inhibits the proliferation and PGE(2) production by fibroblast-like synovial cells (FLS). 
|In vivo||Oral administration of ZSTK474 inhibits the growth of subcutaneously implanted mouse B16F10 melanoma tumors in a dose-dependent manner, producing tumor regression of 28.5%, 7.1%, or 4.9% on day 14 at 100, 200, or 400 mg/kg, respectively, which is superior to that of the four major anticancer drugs irinotecan, cisplatin, doxorubicin, and 5-fluorouracil at their respective maximum tolerable doses with tumor regression of 96%, 35.7%, 24%, or 68.3%, respectively. ZSTK474 treatment at 400 mg/kg completely inhibits the growth of A549, PC-3, and WiDr xenografts in mice, and induces the regression of A549 xenograft tumors.  ZSTK474 significantly inhibits tumor growth in the RXF-631L xenograft model, correlated with a significantly reduced number of microvessels in the ZSTK474-treated mice.  Oral administration of ZSTK474 ameliorates the progression of adjuvant-induced arthritis (AIA) in rats. |
Inhibition of PI3K activity:A549 cells are lysed in a buffer containing 20 mM Tris-HCl (pH 7.5), 150 mM NaCl, 5 mM EDTA, and 1% Igepal CA-630, the lysates are centrifuged at 20,000 g and 4 °C for 10 minutes, and the supernatants are used as cell lysate (protein = 2-4 mg/mL). To immunoprecipitate PI3K, 200 μL of cell lysate are incubated with anti-p85 polyclonal antibody and protein G-agarose (5 μL). PI3Kα, PI3Kβ, and PI3Kδ can be immunoprecipitated by the anti-p85 polyclonal antibody. Agarose beads containing immunoprecipitates are washed twice with buffer A (20 mM Tris-HCl at pH 7.5, 150 mM NaCl, 5 mM EDTA, and 1% Igepal CA-630), once with buffer B (500 mM LiCl and 100 mM Tris-HCl at pH 7.5), once with distilled water, and once with buffer C (100 mM NaCl and 20 mM Tris-HCl at pH 7.5). Immunoprecipitates are suspended in 20 μL of buffer C containing phosphatidylinositol of 200 μg/mL. The mixture is preincubated with increasing concentrations of ZSTK474 at 25 °C for 5 minutes. [γ-32P]ATP (2 μCi per assay mixture; final concentration, 20 μM) and MgCl2 (final concentration, 20 mM) are added to start the reaction. The reaction mixture is incubated at 25 °C for 20 minutes. Phosphorylated products of phosphatidylinositol are separated by thin-layer chromatography and visualized by autoradiography. The phosphatidylinositol-3-phosphate region is scraped from the plate, and radioactivity is also measured with liquid scintillation spectroscopy. The level of inhibition for ZSTK474 is determined as the percentage of 32P counts per minute obtained without ZSTK474.
-  Yaguchi S, et al. J Natl Cancer Inst, 2006, 98(8), 545-556.
-  Kong D, et al. Cancer Sci, 2007, 98(10), 1638-1642.
-  Kong D, et al. Eur J Cancer, 2009, 45(5), 857-865.
|In vitro||DMSO||21 mg/mL (50.31 mM)|
|In vivo||0.5% hydroxyethyl cellulose||30mg/mL|
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