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3103899 
Journal Article 
DW09849, a Selective Phosphatidylinositol 3-Kinase (PI3K) Inhibitor, Prevents PI3K Signaling and Preferentially Inhibits Proliferation of Cells Containing the Oncogenic Mutation p110 alpha (H1047R) 
Liu, J; Gao, G; Zhang, Xi; Cao, S; Guo, CL; Wang, X; Tong, L; Ding, J; Duan, W; Meng, L 
2014 
Yes 
Journal of Pharmacology and Experimental Therapeutics
ISSN: 0022-3565
EISSN: 1521-0103 
348 
432-441 
English 
Phosphatidylinositol 3-kinase, alpha isoform (PI3K alpha) 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 alpha-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 alpha. A series of compounds named DW series potently inhibited the kinase activity of PI3K alpha 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 PI3Ka among four class I PI3K isoforms, whereas a representative compound DW09849 [(E)-N'-((6-bromoimidazo[1,2-a]pyridin-3-yl)methylene)-N-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 G(1) phase. Moreover, DW09849 selectively suppressed the proliferation and clonogenesis of transformed RK3E/HR cells harboring oncogenic mutation of p110 alpha H1047R, as well as a panel of human breast cancer cells containing mutated PI3K alpha, which is consistent with the finding that DW09849 demonstrated preference against H1047R mutated PI3K alpha in molecular docking stimulation. These results suggest that DW series compounds, especially DW09849, selectively targeting PI3K alpha with less off-target effects than PIK-75, provide new clues for the design and discovery of new specific PI3K alpha inhibitors for cancer therapy.