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].