生物活性

• 靶点

  PI3Kα IC50:16nM

  PI3Kβ IC50:44nM

  PI3Kγ IC50:49nM

  PI3Kδ IC50:4.6nM

• 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
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  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

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• 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 ... more >> National Cancer Center Hospital East Kashiwa-city, Chiba, Japan The Cancer Institute Hospital of JFCR Koto-ku, Tokyo, Japan Collapse <<
  NCT01280487	Neoplasms	Phase 1	Completed	-	United States, Massachusetts ... more >> 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 Collapse <<

• 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