Phosphatidylinositol 3-kinase, α
isoform (PI3Kα) 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 PI3Kα-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 PI3Kα. A series of compounds named DW series potently inhibited the
kinase activity of PI3Kα 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 PI3Kα 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 G1 phase. Moreover,
DW09849 selectively suppressed the proliferation and clonogenesis of transformed RK3E/HR cells harboring oncogenic mutation of p110α H1047R, as well as a panel of human
breast cancer cells containing mutated PI3Kα, which is consistent with the finding that
DW09849 demonstrated preference against H1047R mutated PI3Kα in molecular docking stimulation. These results suggest that DW series compounds, especially
DW09849, selectively targeting PI3Kα with less off-target effects than
PIK-75, provide new clues for the design and discovery of new specific PI3Kα inhibitors for
cancer therapy.