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.

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In DMSO USD 90 In stock
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USD 270 In stock
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Cited by 24 Publications

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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 MkTXSpVv[3Srb36gZZN{[Xl? NXLBVIxJOSCq MVvJcohq[mm2aX;uJI9nKGKxdnnu[UBz\WOxbXLpcoFvfCCSSUPLJJAyOTCmZXz0ZUBmgHC{ZYPz[YQhcW5iU3[yNUBqdnOnY4SgZ4VtdHNidYPpcocheGixc4DoZZRq\HmuaX7vd4l1d2xiYYOgd5Vje3S{YYTlJIFnfGW{IEGgbJIh[nlicHjvd5Bpd2mvYXfpcoctKEmFNUC9NE44KG6P MnjGNlE5QDJ6M{K=
human HCT116 cells MWjGeY5kfGmxbjDhd5NigQ>? NWfK[IM4OTVibXnudy=> MVrJcohq[mm2aX;uJI9nKFCLS{PDRUBJOTB2N2KgcZV1[W62LX3l[IlifGWmIHPlcIwhe2mpbnHsbY5oKGmwIHj1cYFvKEiFVEGxOkBk\WyuczDlfJBz\XO|aX7nJHBVTU5iYYPz[ZN{\WRiYYOgbY5pcWKrdHnvckBw\iCrboP1cIlvNWmwZIXj[YQheEGtdD;QT2IheGixc4Doc5J6dGG2aX;uJIF1KFSqckOwPEB1emWjdHXkJIZweiBzNTDtbY5{KGKnZn;y[UBqdnO3bHnuJINp[WyuZX7n[UBu\WG|dYLl[EBi\nSncjC1JI1qdnNiYomgbY1ufW6xYnzveJRqdmduIFnDOVA:Pzhibl2= NYnvUWpZOjF6OEK4N|I>
human LNCAP cells M4[zUHBzd2yrZnXyZZRqd25iYYPzZZk> NWnpcZBIOyCmYYnz NHzWO3ZCdnSrcILvcIln\XKjdHn2[UBi[3Srdnn0fUBi\2GrboP0JIh2dWGwIFzOR2FRKGOnbHzzJIFnfGW{IEOg[IF6eyCkeTDNWHMh[XO|YYmsJGlEPTB;MD6yNUDPxE1? NH;DVVMzODJ{N{i4NS=>
human NZB5 cells NVW4NGJzWHKxbHnm[ZJifGmxbjDhd5NigQ>? NVLsS5lbPSCmYYnz M1TydmFvfGmycn;sbYZmemG2aY\lJIFkfGm4aYT5JIFo[Wmwc4SgbJVu[W5iTmrCOUBk\WyuczDlfJBz\XO|aX7nJJdqdGRidInw[UBxOTFyYXzwbIEh[XO|ZYPz[YQh[XNiaX7jc5Jxd3KjdHnvckBw\iCdM1jdeIh6dWmmaX7lJIFnfGW{IEWg[IF6eyxiSVO1NF0xNjJ{IN88US=> MmHrNlE5QDJ6M{K=
human NZOV9 cells MUDQdo9tcW[ncnH0bY9vKGG|c3H5 NIqwUHQ2KGSjeYO= MXTBcpRqeHKxbHnm[ZJifGm4ZTDhZ5Rqfmm2eTDh[4FqdnO2IHj1cYFvKE6cT2[5JINmdGy|IHX4dJJme3OrbnegdFEyOGGucHjhJItqdmG|ZTDZNVAzOUNibYX0ZY51KGG|c3Xzd4VlKGG|IHnuZ49zeG:{YYTpc44hd2ZiW{PIYZRpgW2rZHnu[UBi\nSncjC1JIRigXNuIFnDOVA:OC5{OTFOwG0> MVmyNVg5Ojh|Mh?=
human MDA-MB-468 cells NX;2cI5vS3m2b4TvfIlkyqCjc4PhfS=> NHv0TWg1QCCq NY\iOHF3S3m2b4TvfIlkcXS7IHHnZYlve3RiUGTFUk1l\W[rY3nlcpQhcHWvYX6gUWRCNU2ELUS2PEBk\WyuczDhd5Nme3OnZDDhd{BqdmirYnn0bY9vKG:oIHPlcIwh\3Kxd4ToJIFnfGW{IES4JIhzeyCkeTDD[YxtKFSrdHXyJFk3KGG|c3H5 NGHreWozOzd7NUKzPS=>
human A549 cells NFLqe5ZHfW6ldHnvckBie3OjeR?= M3rPZ|ExKM7:TR?= MofFNUBp NE\xeHhKdmirYnn0bY9vKG:oIGDJN2shcW5iaIXtZY4hSTV2OTDj[YxteyCjc4Pld5Nm\CCjczDy[YR2[3Srb36gbY4heEGtdDDs[ZZmdCCjdDCxNEB2VSCjZoTldkAyKGi{IHL5JHdme3Sncn6gZoxwfHSrbnegZY5idHm|aYO= Moe5NlU4PjZ4M{O=
human DMS114 cells NIHWe2FIem:5dHigbY5pcWKrdHnvckBie3OjeR?= MnO4S5Jwf3SqIHnubIljcXSrb36gc4YhcHWvYX6gSG1UOTF2IHPlcIx{ MWqyNlM{PjJ2Nh?=
human MKN74 cells NWnX[otJT3Kxd4ToJIlvcGmkaYTpc44h[XO|YYm= NEThRW9Iem:5dHigbY5pcWKrdHnvckBw\iCqdX3hckBOU055NDDj[Yxtew>? MlfmNlI{OzZ{NE[=
human SNB78 cells NIXISnZIem:5dHigbY5pcWKrdHnvckBie3OjeR?= NHzacZpIem:5dHigbY5pcWKrdHnvckBw\iCqdX3hckBUVkJ5ODDj[Yxtew>? MYKyNlM{PjJ2Nh?=
human St-4 cells M1nSXmdzd3e2aDDpcohq[mm2aX;uJIF{e2G7 NGLMSIlIem:5dHigbY5pcWKrdHnvckBw\iCqdX3hckBUfC12IHPlcIx{ M1m2[FIzOzN4MkS2
human DU145 cells NHu4SFhIem:5dHigbY5pcWKrdHnvckBie3OjeR?= NX;ZS5pET3Kxd4ToJIlvcGmkaYTpc44hd2ZiaIXtZY4hTFVzNEWgZ4VtdHN? M3zNN|IzOzN4MkS2
human LOXIMVI cells NGD0VmNIem:5dHigbY5pcWKrdHnvckBie3OjeR?= MX7Hdo94fGhiaX7obYJqfGmxbjDv[kBpfW2jbjDMU3hKVV[LIHPlcIx{ MWeyNlM{PjJ2Nh?=
human PC3 cells MXHHdo94fGhiaX7obYJqfGmxbjDhd5NigQ>? NYPSO5czT3Kxd4ToJIlvcGmkaYTpc44hd2ZiaIXtZY4hWEN|IHPlcIx{ M2LKclIzOzN4MkS2
human LOXIMVI cells NU\CTXVDT3Kxd4ToJIlvcGmkaYTpc44h[XO|YYm= MkHuS5Jwf3SqIHnubIljcXSrb36gc4YhcHWvYX6gUG9ZUU2YSTDj[Yxtew>? MW[yNlM{PjJ2Nh?=
human OVCAR3 cells M4XQeWdzd3e2aDDpcohq[mm2aX;uJIF{e2G7 NFHKd5BIem:5dHigbY5pcWKrdHnvckBw\iCqdX3hckBQXkODUkOgZ4VtdHN? M2D1R|IzOzN4MkS2
human SKOV3 cells MV3Hdo94fGhiaX7obYJqfGmxbjDhd5NigQ>? M2KzeWdzd3e2aDDpcohq[mm2aX;uJI9nKGi3bXHuJHNMV1Z|IHPlcIx{ MoDMNlI{OzZ{NE[=
human KM12 cells MWDHdo94fGhiaX7obYJqfGmxbjDhd5NigQ>? M{\Wemdzd3e2aDDpcohq[mm2aX;uJI9nKGi3bXHuJGtOOTJiY3XscJM> M{L6SVIzOzN4MkS2
human HT-29 cells NVe5R21DT3Kxd4ToJIlvcGmkaYTpc44h[XO|YYm= M{HjNWdzd3e2aDDpcohq[mm2aX;uJI9nKGi3bXHuJGhVNTJ7IHPlcIx{ MnPsNlI{OzZ{NE[=
human HCT15 cells MoLtS5Jwf3SqIHnubIljcXSrb36gZZN{[Xl? NIPHOHVIem:5dHigbY5pcWKrdHnvckBw\iCqdX3hckBJS1RzNTDj[Yxtew>? NEjFbYUzOjN|NkK0Oi=>
human NCI-H226 cells MoiyS5Jwf3SqIHnubIljcXSrb36gZZN{[Xl? M3[zXmdzd3e2aDDpcohq[mm2aX;uJI9nKGi3bXHuJG5EUS2KMkK2JINmdGy| M3XMSFIzOzN4MkS2
human NCI-H522 cells  MmO1S5Jwf3SqIHnubIljcXSrb36gZZN{[Xl? NIf1UGxIem:5dHigbY5pcWKrdHnvckBw\iCqdX3hckBPS0lvSEWyNkBk\Wyuc9Mg MWCyNlM{PjJ2Nh?=
human A549 cells NIqwUFdIem:5dHigbY5pcWKrdHnvckBie3OjeR?= M4TvXmdzd3e2aDDpcohq[mm2aX;uJI9nKGi3bXHuJGE2PDliY3XscJM> MWKyNlM{PjJ2Nh?=
human HCC2998 cells MlfZS5Jwf3SqIHnubIljcXSrb36gZZN{[Xl? NVHRNVBHT3Kxd4ToJIlvcGmkaYTpc44hd2ZiaIXtZY4hUEOFMkm5PEBk\Wyucx?= M4W4TlIzOzN4MkS2
human SNB75 cells NFPadFZIem:5dHigbY5pcWKrdHnvckBie3OjeR?= NEPYS2dIem:5dHigbY5pcWKrdHnvckBw\iCqdX3hckBUVkJ5NTDj[Yxtew>? MVGyNlM{PjJ2Nh?=
human OVCAR4 cells M1OxUWdzd3e2aDDpcohq[mm2aX;uJIF{e2G7 NYTWdXpIT3Kxd4ToJIlvcGmkaYTpc44hd2ZiaIXtZY4hV1[FQWK0JINmdGy| NHuzVIczOjN|NkK0Oi=>
human OVCAR5 cells NXzj[Fl[T3Kxd4ToJIlvcGmkaYTpc44h[XO|YYm= NHjmNpZIem:5dHigbY5pcWKrdHnvckBw\iCqdX3hckBQXkODUkWgZ4VtdHN? Mo\BNlI{OzZ{NE[=
human OVCAR8 cells MmD4S5Jwf3SqIHnubIljcXSrb36gZZN{[Xl? Mo\VS5Jwf3SqIHnubIljcXSrb36gc4YhcHWvYX6gU3ZESVJ6IHPlcIx{ NXXpOVJ4OjJ|M{[yOFY>
human SKOV3 cells M1qyV2dzd3e2aDDpcohq[mm2aX;uJIF{e2G7 NGj6[WRIem:5dHigbY5pcWKrdHnvckBw\iCqdX3hckBUU0:YMzDj[Yxtew>? NULpNVVtOjJ|M{[yOFY>
human ACHN cells Mn3uS5Jwf3SqIHnubIljcXSrb36gZZN{[Xl? MkHJS5Jwf3SqIHnubIljcXSrb36gc4YhcHWvYX6gRWNJViClZXzsdy=> NGHWeY8zOjN|NkK0Oi=>

... Click to View More Cell Line Experimental Data

Assay
Methods Test Index PMID
Western blot
p-PDK1 / p-GSK3β / p-AKT / AKT ; 

PubMed: 28388564     


ZSTK474 inhibited PI3K/Akt pathway in HL60 and HL60/ADR cells. HL60 and HL60/ADR cells were cultured in the presence of various concentrations of ZSTK474 for 48 h. The cells were collected, and the cell lysates were prepared to be available for Western blot analysis of p-PDK1, p-Akt, Akt, p-GSK-3β, and β-actin levels.

P-gp / MRP1 ; 

PubMed: 28388564     


ZSTK474 inhibited expression of P-gp and MRP1. HL60/ADR cells were cultured in the presence of indicated concentrations of ZSTK474 for 48 h. The cells were collected for Western blot analysis of P-gp and MRP1 levels. 

p-Rb / p27 / Cyclin D1 ; 

PubMed: 26918351     


The cells were treated with 0, 0.1, 0.5, 2, 4 μM of ZSTK474 for 24 h. After treatment, the lysates of whole cell or nucleus were prepared by using the respective lysis buffer, to be available for western blot. The blots were exposed to anti- cyclin D1, p-GSK-3β, p27, phosphorylated p-Rb, β-actin (for whole cell) or Lamin B (for nucleus).

HIF-1α / HIF-1β ; 

PubMed: 23812078     


ZSTK474 inhibits the expression of hypoxia inducible factor-1 (HIF-1)α in PC3 cells. The expression levels of HIF-1α, HIF-1β and β-actin in the cell lysates prepared from the DMSO-treated and ZSTK474-treated PC3 cells were determined by western blot analysis. β-actin expression was determined for a quantitative control of protein amount

28388564 26918351 23812078
Growth inhibition assay
Cell viability; 

PubMed: 28388564     


(A) HL60/ADR cells showed resistance to ADR. Cell viability was determined via MTT assay after treatment with various concentrations of ADR for 48 h. (B) ZSTK474 inhibited the proliferation of both HL60 and HL60/ADR cells in a dose-dependent manner. The cells were treated with various concentrations of ZSTK474 for 48 h, and cell viability was determined by MTT assay. Data are presented as mean ± SD and are representative of three independent experiments.

28388564
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]
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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]
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  • 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]
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  • 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 Insoluble
Ethanol Insoluble
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
0.5% hydroxyethyl cellulose
For best results, use promptly after mixing.
30mg/mL

* 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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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID