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• W2025745090 abstract "Phosphatidylinositol 3-kinase, <i>α</i> isoform (PI3K<i>α</i>) plays essential roles in cell metabolism, growth, and proliferation and has been validated as a promising anticancer target. In an effort to search for new PI3K<i>α</i>-selective inhibitors, DW series compounds were designed and synthesized aiming to reduce the off-target effects of their parent compound PIK-75 [2-methyl-5-nitro-1-benzenesulfonic acid 2-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-1-methylhydrazide], which was reported to selectively target PI3K<i>α</i>. A series of compounds named DW series potently inhibited the kinase activity of PI3K<i>α</i> with little activity against PI3K-related protein kinases and a panel of 15 tyrosine kinases. Similar to PIK-75, DW series compounds were more potent to inhibit PI3K<i>α</i> among four class I PI3K isoforms, whereas a representative compound DW09849 [(<i>E</i>)-<i>N</i>′-((6-bromoimidazo[1,2-a]pyridin-3-yl)methylene)-<i>N</i>-ethyl-2-methyl-5-nitrobenzohydrazide] displayed distinct binding mode compared with PIK-75. Although DW series compounds inhibited proliferation of rhabdomyosarcoma RH30 cells at elevated 50% inhibitory concentrations (IC₅₀) in comparison with PIK-75, they were more selective than PIK-75 to inhibit PI3K signaling in the cellular context. In particular, DW09849 significantly and persistently blocked PI3K/protein kinase B signaling in RH30 cells, which consequently arrested RH30 cells in the G₁ phase. Moreover, DW09849 selectively suppressed the proliferation and clonogenesis of transformed RK3E/HR cells harboring oncogenic mutation of p110<i>α</i> H1047R, as well as a panel of human breast cancer cells containing mutated PI3K<i>α</i>, which is consistent with the finding that DW09849 demonstrated preference against H1047R mutated PI3K<i>α</i> in molecular docking stimulation. These results suggest that DW series compounds, especially DW09849, selectively targeting PI3K<i>α</i> with less off-target effects than PIK-75, provide new clues for the design and discovery of new specific PI3K<i>α</i> inhibitors for cancer therapy." @default.
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• W2025745090 date "2013-12-20" @default.
• W2025745090 modified "2023-10-02" @default.
• W2025745090 title "DW09849, a Selective Phosphatidylinositol 3-Kinase (PI3K) Inhibitor, Prevents PI3K Signaling and Preferentially Inhibits Proliferation of Cells Containing the Oncogenic Mutation p110α (H1047R)" @default.
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• W2025745090 doi "https://doi.org/10.1124/jpet.113.210724" @default.
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