ZSTK474

Potent PI3K inhibitor CAS# 475110-96-4

ZSTK474

Catalog No. BCC3657----Order now to get a substantial discount!

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Chemical structure

ZSTK474

3D structure

Chemical Properties of ZSTK474

Cas No. 475110-96-4 SDF Download SDF
PubChem ID 11647372 Appearance Powder
Formula C19H21F2N7O2 M.Wt 417.41
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 2 mg/mL (4.79 mM; Need ultrasonic)
Chemical Name 4-[4-[2-(difluoromethyl)benzimidazol-1-yl]-6-morpholin-4-yl-1,3,5-triazin-2-yl]morpholine
SMILES C1COCCN1C2=NC(=NC(=N2)N3C4=CC=CC=C4N=C3C(F)F)N5CCOCC5
Standard InChIKey HGVNLRPZOWWDKD-UHFFFAOYSA-N
Standard InChI InChI=1S/C19H21F2N7O2/c20-15(21)16-22-13-3-1-2-4-14(13)28(16)19-24-17(26-5-9-29-10-6-26)23-18(25-19)27-7-11-30-12-8-27/h1-4,15H,5-12H2
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of ZSTK474

DescriptionZSTK474 is inhibitor of class I PI3K isoforms with an IC50 of 37 nM.
TargetsPI3KδPI3KαPI3KPI3KβPI3Kγ  
IC504.6 nM16 nM37 nM44 nM49 nM  

Protocol

Kinase Assay [1]
The linear phase of each kinetic reaction is defined at the respective enzyme amount (0.05, 0.1, 0.12 and 1 µg/mL for PI3Kα, PI3β, PI3δ and PI3γ, respectively) and reaction time (20 min). PI3K activity is assayed at various concentrations of ATP (5, 10, 25, 50, 100 µM) in the presence of increasing concentrations of ZSTK474. A Lineweaver-Burk plot is developed by plotting 1/v (the inverse of v, where v is obtained by subtracting the HTRF signal of the kinase test sample from the HTRF signal of the minus-enzyme control) versus 1/[ATP] (the inverse of the ATP concentration). For the minus-enzyme control, PIP2 is incubated with ATP in the absence of kinase. To determine the Ki value (inhibition constant) of ZSTK474 for each PI3K isoform, the slope of the respective Lineweaver-Burk plot is replotted against the ZSTK474 concentration. The Ki values are calculated by analysis using GraphPad Prism 4[1].

Animal Administration [2]
Mice[2] Mice are randomly assigned to receive different doses of ZSTK474 (50, 100, 200, and 300 mg/kg) to determine the optimum dose; in our experiment, the optimum dose is 200 mg/kg. Then mice are randomly assigned to one of three groups: a sham-operated group (phosphate-buffered saline, PBS); a control group (MCAO+PBS); a ZSTK474-treated group (MCAO+ZSTK474). In the ZSTK474-treated group, the mice are given the optimum dose of 200 mg/kg ZSTK474. In the sham-operated group and control group, mice are given an equivalent volume of PBS. All mice receive that same dose daily via oral gavage beginning at 6 h after the onset of focal ischemia and continuing for two more days, i.e., for a total of 3 days.

References:
[1]. Kong D, et al. ZSTK474 is an ATP-competitive inhibitor of class I phosphatidylinositol 3 kinase isoforms. Cancer Sci, 2007, 98(10), 1638-1642. [2]. Wang P, et al. Class I PI3K inhibitor ZSTK474 mediates a shift in microglial/macrophage phenotype and inhibits inflammatory response in mice with cerebral ischemia/reperfusion injury. J Neuroinflammation. 2016 Aug 22;13(1):192. [3]. Liu F, et al. Prolonged inhibition of class I PI3K promotes liver cancer stem cell expansion by augmenting SGK3/GSK-3β/β-catenin signalling. J Exp Clin Cancer Res. 2018 Jun 25;37(1):122.

ZSTK474 Dilution Calculator

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Preparing Stock Solutions of ZSTK474

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.3957 mL 11.9786 mL 23.9573 mL 47.9145 mL 59.8932 mL
5 mM 0.4791 mL 2.3957 mL 4.7915 mL 9.5829 mL 11.9786 mL
10 mM 0.2396 mL 1.1979 mL 2.3957 mL 4.7915 mL 5.9893 mL
50 mM 0.0479 mL 0.2396 mL 0.4791 mL 0.9583 mL 1.1979 mL
100 mM 0.024 mL 0.1198 mL 0.2396 mL 0.4791 mL 0.5989 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on ZSTK474

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]
References:
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.

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References on ZSTK474

ZSTK474, a specific class I phosphatidylinositol 3-kinase inhibitor, induces G1 arrest and autophagy in human breast cancer MCF-7 cells.[Pubmed:26918351]

Oncotarget. 2016 Apr 12;7(15):19897-909.

Multifaceted activities of class I phosphatidylinositol 3-kinase (PI3K) inhibitor ZSTK474 were investigated on human breast cancer cell MCF-7. ZSTK474 inhibited proliferation of MCF-7 cells potently. Flow cytometric analysis indicated that ZSTK474 induced cell cycle arrest at G1 phase, but no obvious apoptosis occurred. Western blot analysis suggested that blockade of PI3K/Akt/GSK-3beta/cyclin D1/p-Rb pathway might contribute to the G1 arrest induced. Moreover, we demonstrated that ZSTK474 induced autophagy in MCF-7 cells by use of various assays including monodansylcadaverine (MDC) staining, transmission electron microscopy (TEM), tandem mRFP-GFP-LC3 fluorescence microscopy, and western blot detection of the autophagy protein markers of LC3B II, p62 and Atg 5. Inhibition of class I PI3K and the downstream mTOR might be involved in the autophagy-inducing effect. Combinational use of ZSTK474 and autophagy inhibitors enhanced cell viability, suggesting ZSTK474-induced autophagy might contribute to the antitumor activity. Our report supports the application of ZSTK474, which is being evaluated in clinical trials, for breast cancer therapy.

In Vitro Antileukemia Activity of ZSTK474 on K562 and Multidrug Resistant K562/A02 Cells.[Pubmed:27194941]

Int J Biol Sci. 2016 Apr 8;12(6):631-8.

Chronic myelogenous leukemia (CML) is a malignant hematological disorder mainly caused by the Bcr-Abl tyrosine kinase. While Bcr-Abl inhibitors including Imatinib showed antitumor efficacy on many CML patients, resistance was frequently reported in recent years. Therefore, novel drugs for CML are still expected. ZSTK474 is a specific phosphatidylinositol 3-kinase (PI3K) inhibitor that we identified. In the present study, the efficacy of ZSTK474, alone or in combination with Imatinib, on K562 CML cells as well as on its multidrug resistance counterpart K562/A02 cells, was investigated. ZSTK474 inhibited the cell proliferation with an IC50 of 4.69 muM for K562 and 7.57 muM for K562/A02 cells, respectively. Treatment by ZSTK474 resulted in cell cycle arrest in G1 phase, which might be associated with upregulation of p27, and downregulation of cyclin D1. ZSTK474 also inhibited phosphorylation of Akt and GSK-3beta, which might be involved in the effect on the above cell cycle-related proteins. Moreover, combination of ZSTK474 and Imatinib indicated synergistic effect on both cell lines. In conclusion, ZSTK474 exhibited antileukemia activity alone, and showed synergistic effect when combined with Imatinib, on CML K562 cells as well as the multidrug resistant ones, providing a potential therapeutic approach for CML patients.

Synergistic antitumour activity of RAF265 and ZSTK474 on human TT medullary thyroid cancer cells.[Pubmed:26081844]

J Cell Mol Med. 2015 Sep;19(9):2244-52.

Medullary thyroid cancer (MTC) is an aggressive malignancy responsible for up to 14% of all thyroid cancer-related deaths. It is characterized by point mutations in the rearranged during transfection (RET) proto-oncogene. The activated RET kinase is known to signal via extracellular signal regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K), leading to enhanced proliferation and resistance to apoptosis. In the present work, we have investigated the effect of two serine/threonine-protein kinase B-Raf (BRAF) inhibitors (RAF265 and SB590885), and a PI3K inhibitor (ZSTK474), on RET-mediated signalling and proliferation in a MTC cell line (TT cells) harbouring the RETC634W activating mutation. The effects of the inhibitors on VEGFR2, PI3K/Akt and mitogen-activated protein kinases signalling pathways, cell cycle, apoptosis and calcitonin production were also investigated. Only the RAF265+ ZSTK474 combination synergistically reduced the viability of treated cells. We observed a strong decrease in phosphorylated VEGFR2 for RAF265+ ZSTK474 and a signal reduction in activated Akt for ZSTK474. The activated ERK signal also decreased after RAF265 and RAF265+ ZSTK474 treatments. Alone and in combination with ZSTK474, RAF265 induced a sustained increase in necrosis. Only RAF265, alone and combined with ZSTK474, prompted a significant drop in calcitonin production. Combination therapy using RAF265 and ZSTK47 proved effective in MTC, demonstrating a cytotoxic effect. As the two inhibitors have been successfully tested individually in clinical trials on other human cancers, our preclinical data support the feasibility of their combined use in aggressive MTC.

Class I PI3K inhibitor ZSTK474 mediates a shift in microglial/macrophage phenotype and inhibits inflammatory response in mice with cerebral ischemia/reperfusion injury.[Pubmed:27549161]

J Neuroinflammation. 2016 Aug 22;13(1):192.

BACKGROUND: Microglia/macrophages play a critical role in the inflammatory and immune processes of cerebral ischemia/reperfusion injury. Since microglia/macrophages can reversibly shift their phenotype toward either a "detrimental" or a "restorative" state in the injured central nervous system (CNS), compounds mediate that shift which could inhibit inflammation and restore the ability to alleviate cerebral ischemia/reperfusion injury would have therapeutic potential. METHODS: Transient middle cerebral artery occlusion was induced in male C57BL/6 mice. Mice were randomly separated into a sham-operated group, a control group, and a ZSTK474-treated group. We investigated the effect of ZSTK474 by assessing neurological deficits, infarct volume, and histopathological changes. We then determined the potential mechanism by immunofluorescent staining, quantitative real-time polymerase chain reaction (PCR), and Western blot analysis. The Tukey's test or Mann-Whitney U test was used to compare differences among the groups. RESULTS: ZSTK474 alleviated neurological deficits and reduced infarct volume in the cerebral ischemia/reperfusion injury model. Presumably, ZSTK474 shifted the phenotype of microglia/macrophages to a restorative state, since this treatment decreased the secretion of pro-inflammatory factors and advanced the secretion of anti-inflammatory factors. These neuroprotective properties of ZSTK474 may be mediated by the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin complex 1 (mTORC1) pathway. CONCLUSIONS: ZSTK474 can mediate a shift in microglia/macrophage phenotype and inhibit the inflammatory response in cerebral ischemia reperfusion injury of mice. These effects appeared to ensue via the PI3K/AKT/mTORC1 pathway. Therefore, ZSTK474 may represent a therapeutic intervention with potential for circumventing the catastrophic aftermath of ischemic stroke.

Description

ZSTK474 is an ATP-competitive pan-class I PI3K inhibitor with IC50s of16 nM, 44 nM, 4.6 nM and 49 nM for PΙ3Κα, PI3Kβ, PI3Kδ and PI3Kγ, respectively.

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