ZSTK474

Catalog No.S1072

ZSTK474 Chemical Structure

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.

Size Price Stock Quantity  
In DMSO USD 90 In stock
USD 70 In stock
USD 270 In stock

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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.

  • Western blot analysis of Akt and p-Akt. 0-20μM ZSTK474 was added.

    Dr. Zhang of Tianjin Medical University . ZSTK474 purchased from Selleck.

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Biological Activity

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.
Targets
PI3Kδ [2]
(Cell-free assay)
PI3Kα [2]
(Cell-free assay)
PI3K [1]
(Cell-free assay)
PI3Kβ [2]
(Cell-free assay)
PI3Kγ [2]
(Cell-free assay)
4.6 nM 16 nM 37 nM 44 nM 49 nM
In vitro

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. [1] ZSTK474 does not inhibit mTOR at 0.1 μM, and even at a concentration of 100 μM, ZSTK474 inhibits mTOR activity less than 40%. [2] 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. [3] 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). [6]

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
Sf21 insect cells NF\0T2VHfW6ldHnvckBie3OjeR?= NHLxO2MyKGh? NHjoOXNKdmirYnn0bY9vKG:oIHLveolv\SC{ZXPvcYJqdmGwdDDQTVNMKHBzMUDk[Yx1[SCneIDy[ZN{\WRiaX6gV4YzOSCrboPlZ5Qh[2WubIOgeZNqdmdicHjvd5Bp[XSrZInsbY5we2m2b3ygZZMhe3Wkc4TyZZRmKGGodHXyJFEhcHJiYomgdIhwe3Cqb3ntZYdqdmduIFnDOVA:OC55IH7N MoCzNlE5QDJ6M{K=
human HCT116 cells M1SzeGZ2dmO2aX;uJIF{e2G7 NFjyXogyPSCvaX7z MUDJcohq[mm2aX;uJI9nKFCLS{PDRUBJOTB2N2KgcZV1[W62LX3l[IlifGWmIHPlcIwhe2mpbnHsbY5oKGmwIHj1cYFvKEiFVEGxOkBk\WyuczDlfJBz\XO|aX7nJHBVTU5iYYPz[ZN{\WRiYYOgbY5pcWKrdHnvckBw\iCrboP1cIlvNWmwZIXj[YQheEGtdD;QT2IheGixc4Doc5J6dGG2aX;uJIF1KFSqckOwPEB1emWjdHXkJIZweiBzNTDtbY5{KGKnZn;y[UBqdnO3bHnuJINp[WyuZX7n[UBu\WG|dYLl[EBi\nSncjC1JI1qdnNiYomgbY1ufW6xYnzveJRqdmduIFnDOVA:Pzhibl2= MkjaNlE5QDJ6M{K=
human LNCAP cells NUTsSFJ2WHKxbHnm[ZJifGmxbjDhd5NigQ>? MmjvN{Bl[Xm| NEHEVotCdnSrcILvcIln\XKjdHn2[UBi[3Srdnn0fUBi\2GrboP0JIh2dWGwIFzOR2FRKGOnbHzzJIFnfGW{IEOg[IF6eyCkeTDNWHMh[XO|YYmsJGlEPTB;MD6yNUDPxE1? NInQNXgzODJ{N{i4NS=>
human NZB5 cells NVO2UGh2WHKxbHnm[ZJifGmxbjDhd5NigQ>? MUK1JIRigXN? M3zIeWFvfGmycn;sbYZmemG2aY\lJIFkfGm4aYT5JIFo[Wmwc4SgbJVu[W5iTmrCOUBk\WyuczDlfJBz\XO|aX7nJJdqdGRidInw[UBxOTFyYXzwbIEh[XO|ZYPz[YQh[XNiaX7jc5Jxd3KjdHnvckBw\iCdM1jdeIh6dWmmaX7lJIFnfGW{IEWg[IF6eyxiSVO1NF0xNjJ{IN88US=> M{TnW|IyQDh{OEOy
human NZOV9 cells M2mzPXBzd2yrZnXyZZRqd25iYYPzZZk> M3O4S|Uh\GG7cx?= NVXERZAySW62aYDyc4xq\mW{YYTpeoUh[WO2aY\peJkh[WejaX7zeEBpfW2jbjDOXm9XQSClZXzsd{BmgHC{ZYPzbY5oKHBzMUDhcJBp[SCtaX7hd4UhYTFyMkHDJI12fGGwdDDhd5Nme3OnZDDhd{BqdmOxcoDvdoF1cW:wIH;mJHs{UF22aIntbYRqdmViYX\0[ZIhPSCmYYnzMEBKSzVyPUCuNlkh|ryP M3m0bVIyQDh{OEOy
human MDA-MB-468 cells MnLrR5l1d3SxeHnjxsBie3OjeR?= NUn3NJVpPDhiaB?= NFfoRZpEgXSxdH;4bYNqfHliYXfhbY5{fCCSVFXOMYRm\mmlaXXueEBpfW2jbjDNSGEuVUJvNE[4JINmdGy|IHHzd4V{e2WmIHHzJIlvcGmkaYTpc44hd2ZiY3XscEBoem:5dHigZYZ1\XJiNEigbJJ{KGK7IFPlcIwhXGm2ZYKgPVYh[XO|YYm= NF;wPVkzOzd7NUKzPS=>
human A549 cells M{H1eWZ2dmO2aX;uJIF{e2G7 NV74OldLOTBizszN MnrRNUBp MULJcohq[mm2aX;uJI9nKFCLM1ugbY4hcHWvYX6gRVU1QSClZXzsd{Bie3Onc4Pl[EBieyC{ZXT1Z5Rqd25iaX6gdGFsfCCuZY\lcEBifCBzMDD1UUBi\nSncjCxJIhzKGK7IGfld5Rmem5iYnzveJRqdmdiYX7hcJl{cXN? MoHvNlU4PjZ4M{O=
human DMS114 cells MoTCS5Jwf3SqIHnubIljcXSrb36gZZN{[Xl? M1\LTGdzd3e2aDDpcohq[mm2aX;uJI9nKGi3bXHuJGROWzFzNDDj[Yxtew>? NF25ZVgzOjN|NkK0Oi=>
human MKN74 cells MlnhS5Jwf3SqIHnubIljcXSrb36gZZN{[Xl? NF;mWHJIem:5dHigbY5pcWKrdHnvckBw\iCqdX3hckBOU055NDDj[Yxtew>? M1rU[FIzOzN4MkS2
human SNB78 cells NGrRV2lIem:5dHigbY5pcWKrdHnvckBie3OjeR?= MljZS5Jwf3SqIHnubIljcXSrb36gc4YhcHWvYX6gV25DPzhiY3XscJM> NHnhWHMzOjN|NkK0Oi=>
human St-4 cells M3T6XGdzd3e2aDDpcohq[mm2aX;uJIF{e2G7 NHTRUXpIem:5dHigbY5pcWKrdHnvckBw\iCqdX3hckBUfC12IHPlcIx{ NHjtWWgzOjN|NkK0Oi=>
human DU145 cells NVPxVll1T3Kxd4ToJIlvcGmkaYTpc44h[XO|YYm= NEjUcnpIem:5dHigbY5pcWKrdHnvckBw\iCqdX3hckBFXTF2NTDj[Yxtew>? MnnuNlI{OzZ{NE[=
human LOXIMVI cells NUfCWHY{T3Kxd4ToJIlvcGmkaYTpc44h[XO|YYm= NV\2OmpHT3Kxd4ToJIlvcGmkaYTpc44hd2ZiaIXtZY4hVE:[SV3WTUBk\Wyucx?= MmPVNlI{OzZ{NE[=
human PC3 cells NXX1SYk6T3Kxd4ToJIlvcGmkaYTpc44h[XO|YYm= MnfZS5Jwf3SqIHnubIljcXSrb36gc4YhcHWvYX6gVGM{KGOnbHzz NWHzfmdPOjJ|M{[yOFY>
human LOXIMVI cells MUTHdo94fGhiaX7obYJqfGmxbjDhd5NigQ>? MWHHdo94fGhiaX7obYJqfGmxbjDv[kBpfW2jbjDMU3hKVV[LIHPlcIx{ MmryNlI{OzZ{NE[=
human OVCAR3 cells NYji[mFET3Kxd4ToJIlvcGmkaYTpc44h[XO|YYm= NYL6W2xjT3Kxd4ToJIlvcGmkaYTpc44hd2ZiaIXtZY4hV1[FQWKzJINmdGy| MofmNlI{OzZ{NE[=
human SKOV3 cells MX\Hdo94fGhiaX7obYJqfGmxbjDhd5NigQ>? MWjHdo94fGhiaX7obYJqfGmxbjDv[kBpfW2jbjDTT29XOyClZXzsdy=> NYraWJdMOjJ|M{[yOFY>
human KM12 cells MVXHdo94fGhiaX7obYJqfGmxbjDhd5NigQ>? M2DjWGdzd3e2aDDpcohq[mm2aX;uJI9nKGi3bXHuJGtOOTJiY3XscJM> Mmf6NlI{OzZ{NE[=
human HT-29 cells NXnMbFV1T3Kxd4ToJIlvcGmkaYTpc44h[XO|YYm= NUe1O5l7T3Kxd4ToJIlvcGmkaYTpc44hd2ZiaIXtZY4hUFRvMkmgZ4VtdHN? MoW2NlI{OzZ{NE[=
human HCT15 cells NUXiWpFKT3Kxd4ToJIlvcGmkaYTpc44h[XO|YYm= M3fsW2dzd3e2aDDpcohq[mm2aX;uJI9nKGi3bXHuJGhEXDF3IHPlcIx{ Mk\0NlI{OzZ{NE[=
human NCI-H226 cells NUDY[I1vT3Kxd4ToJIlvcGmkaYTpc44h[XO|YYm= MYTHdo94fGhiaX7obYJqfGmxbjDv[kBpfW2jbjDOR2kuUDJ{NjDj[Yxtew>? MnHWNlI{OzZ{NE[=
human NCI-H522 cells  NYXkSIdET3Kxd4ToJIlvcGmkaYTpc44h[XO|YYm= NVrCemF3T3Kxd4ToJIlvcGmkaYTpc44hd2ZiaIXtZY4hVkOLLVi1NlIh[2WubIRCpC=> MYCyNlM{PjJ2Nh?=
human A549 cells NF;FZXlIem:5dHigbY5pcWKrdHnvckBie3OjeR?= MUnHdo94fGhiaX7obYJqfGmxbjDv[kBpfW2jbjDBOVQ6KGOnbHzz NEHrcWszOjN|NkK0Oi=>
human HCC2998 cells MWjHdo94fGhiaX7obYJqfGmxbjDhd5NigQ>? M1PrOWdzd3e2aDDpcohq[mm2aX;uJI9nKGi3bXHuJGhESzJ7OUigZ4VtdHN? MWSyNlM{PjJ2Nh?=
human SNB75 cells MWDHdo94fGhiaX7obYJqfGmxbjDhd5NigQ>? NE\TZoFIem:5dHigbY5pcWKrdHnvckBw\iCqdX3hckBUVkJ5NTDj[Yxtew>? M4W1XlIzOzN4MkS2
human OVCAR4 cells NEnHS4RIem:5dHigbY5pcWKrdHnvckBie3OjeR?= M{Xsbmdzd3e2aDDpcohq[mm2aX;uJI9nKGi3bXHuJG9XS0GUNDDj[Yxtew>? M4n0SFIzOzN4MkS2
human OVCAR5 cells MmTvS5Jwf3SqIHnubIljcXSrb36gZZN{[Xl? M2\CWWdzd3e2aDDpcohq[mm2aX;uJI9nKGi3bXHuJG9XS0GUNTDj[Yxtew>? NV3OdllZOjJ|M{[yOFY>
human OVCAR8 cells M1TqfGdzd3e2aDDpcohq[mm2aX;uJIF{e2G7 NH:yOI1Iem:5dHigbY5pcWKrdHnvckBw\iCqdX3hckBQXkODUkigZ4VtdHN? M4LiZlIzOzN4MkS2
human SKOV3 cells NEW0TJRIem:5dHigbY5pcWKrdHnvckBie3OjeR?= NHzmNmJIem:5dHigbY5pcWKrdHnvckBw\iCqdX3hckBUU0:YMzDj[Yxtew>? MnrYNlI{OzZ{NE[=
human ACHN cells MWfHdo94fGhiaX7obYJqfGmxbjDhd5NigQ>? MUTHdo94fGhiaX7obYJqfGmxbjDv[kBpfW2jbjDBR2hPKGOnbHzz MWCyNlM{PjJ2Nh?=

... Click to View More Cell Line Experimental Data

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. [1] ZSTK474 significantly inhibits tumor growth in the RXF-631L xenograft model, correlated with a significantly reduced number of microvessels in the ZSTK474-treated mice. [3] Oral administration of ZSTK474 ameliorates the progression of adjuvant-induced arthritis (AIA) in rats. [6]

Protocol

Kinase Assay:[1]
+ Expand

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.
Cell Research:[1]
+ Expand
  • Cell lines: MCF-7, HT-29, HCT-116, OVCAR3, A549, et al.
  • Concentrations: Dissolved in DMSO, final concentrations ~10 μM
  • Incubation Time: 48 hours
  • Method: Cells are exposed to increasing concentrations of ZSTK474 for 48 hours. The inhibition of cell proliferation is assessed by measuring changes in total cellular protein by use of a sulforhodamine B assay. Apoptosis is assessed by chromatin condensation or by flow cytometry. For chromatin condensation assay, cells are stained with Hoechst 33342 and examined by fluorescence microscopy. Morphologic changes induced by ZSTK474, such as the condensation of chromatin, are indicative of apoptosis. For flow cytometry analysis, cells are harvested, washed with ice-cold PBS, and fixed in 70% ethanol. Cells are then washed twice with ice-cold PBS again, treated with RNase A (500 μg/mL) at 37 °C for 1 hour, and stained with propidium iodide (25 μg/mL). The DNA content of the cells is analyzed with a flow cytometer.
    (Only for Reference)
Animal Research:[1]
+ Expand
  • Animal Models: Male BDF1 mice injected subcutaneously with B16F10 cells, and female BALB/c nude mice inoculated subcutaneously with A549, PC-3, or WiDr cells
  • Formulation: Suspended in 5% hydroxypropylcellulose in water as a solid dispersion form
  • Dosages: ~400 mg/kg/day
  • Administration: Orally
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 21 mg/mL (50.31 mM)
Water <1 mg/mL
Ethanol <1 mg/mL
In vivo 0.5% hydroxyethyl cellulose 30mg/mL

* 1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 417.41
Formula

C19H21F2N7O2

CAS No. 475110-96-4
Storage powder
in solvent
Synonyms N/A

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT01682473 Unknown status Neoplasms Zenyaku Kogyo Co., Ltd. September 2012 Phase 1
NCT01280487 Completed Neoplasms Zenyaku Kogyo Co., Ltd. January 2011 Phase 1

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID