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ZSTK474

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Chemical Structure| 475110-96-4 同义名 : -
CAS号 : 475110-96-4
货号 : A156873
分子式 : C19H21F2N7O2
纯度 : 98%
分子量 : 417.413
MDL号 : MFCD08705334
存储条件：

粉末 Sealed in dry,Store in freezer, under -20°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 2 mg/mL(4.79 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：

0.5% hydroxyethyl cellulose+water 30 mg/mL suspension

生物活性
靶点

  • p110γ

    PI3Kγ, IC50:49 nM

  • p110β

    PI3Kβ, IC50:44 nM

  • p110α

    PI3Kα, IC50:16 nM

  • PI3K

    PI3K, IC50:37 nM

  • p110δ

    PI3Kδ, IC50:4.6 nM
描述 Phosphatidylinositol 3-kinase (PI3K), which is active in signal transduction, generates phosphatidylinositol-3,4,5-tris-phosphate (PIP3) by phosphorylating phosphatidylinositol-4,5-bisphosphate. PI3K is involved in various cellular processes, including cell survival, vesicle transport, and cytoskeletal rearrangement[3]. ZSTK474, a novel s-triazine derivative, is an ATP-competitive pan-class I PI3K inhibitor with IC50s of 16 nM, 44 nM, 4.6 nM and 49 nM for PΙ3Κα, PI3Kβ, PI3Kδ and PI3Kγ, respectively[4]. The mean logarithm of GI50 for ZSTK474 was −6.49 at 0.32 μM, which was substantially lower than that observed with LY294002 or wortmannin, indicating that ZSTK474 had stronger cell growth inhibitory activity than either of these two known PI3K inhibitors. At concentration of 1 μM, ZSTK474 reduced the PI3K activity to 4.7% of the untreated control activity. When murine embryonic fibroblast cells were incubated for 15 minutes with 1 μM ZSTK474 before the addition of platelet-derived growth factor, both membrane ruffling and the formation of PIP3 , a measure of PI3K activity, were blocked. At 10 μM, a higher concentration than its GI50, ZSTK474 induced apoptosis in OVCAR3 cells. When administered orally for 2 weeks, ZSTK474 inhibited the growth of subcutaneously implanted mouse B16F10 melanoma tumors in a dose-dependent manner. Almost complete tumor growth inhibition (i.e., tumor regression) was observed at higher dosages[3].
作用机制 There are three hydrogen-bonding interactions between PI3K and ZSTK474 (i.e., K802 NZ, one of the morpholino oxygens; S806 OG, the other morpholino oxygen; and V882 NH, the benzimidazole nitrogen)[3].
细胞研究
细胞系 浓度 检测类型 检测时间 活动说明 数据源
human A549 cells 10 μM Function assay 1 h Inhibition of PI3K in human A549 cells assessed as reduction in pAkt level at 10 uM after 1 hr by Western blotting analysis 25766633
human A549 cells Growth inhibition assay Growth inhibition of human A549 cells 22336246
human ACHN cells Growth inhibition assay Growth inhibition of human ACHN cells 22336246
临床研究
NCT号 适应症或疾病 临床期 招募状态 预计完成时间 地点
NCT01682473 Neoplasms Phase 1 Completed - Japan ... 展开 >> National Cancer Center Hospital East Kashiwa-city, Chiba, Japan The Cancer Institute Hospital of JFCR Koto-ku, Tokyo, Japan 收起 <<
NCT01280487 Neoplasms Phase 1 Completed - United States, Massachusetts ... 展开 >> Dana Farber Cancer Institute Boston, Massachusetts, United States United States, Missouri Washington University St Louis, Missouri, United States United States, Pennsylvania Fox Chase Cancer Center Philadelphia, Pennsylvania, United States 收起 <<
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.40mL

0.48mL

0.24mL

11.98mL

2.40mL

1.20mL

23.96mL

4.79mL

2.40mL
参考文献

[1]Kong D, Okamura M, Yoshimi H, Yamori T. Antiangiogenic effect of ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor. Eur J Cancer. 2009 Mar;45(5):857-65.

[2]Kong D, Yamori T. ZSTK474 is an ATP-competitive inhibitor of class I phosphatidylinositol 3 kinase isoforms. Cancer Sci. 2007 Oct;98(10):1638-42.

[3]Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor

[4]ZSTK474 is an ATP-competitive inhibitor of class I phosphatidylinositol 3 kinase isoforms