ABSTRACT
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.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Class Ia Phosphatidylinositol 3-Kinase/metabolism , Heterocyclic Compounds, 2-Ring/pharmacology , Hydrazones/pharmacology , Oncogenes , Phosphoinositide-3 Kinase Inhibitors , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Transformed , Cell Line, Tumor , Class Ia Phosphatidylinositol 3-Kinase/genetics , G1 Phase Cell Cycle Checkpoints , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/chemistry , Humans , Hydrazones/chemical synthesis , Hydrazones/chemistry , Models, Molecular , Mutation , Rats , Signal Transduction , Structure-Activity Relationship , TOR Serine-Threonine Kinases/metabolismABSTRACT
In the title compound, C(10)H(9)N(5), the fused 2-methyl-imidazo[1,2-a]pyrimidine ring system is approximately planar [dihedral angle of 1.14â (9)° between the two fused rings] and the 1H-pyrazole ring is rotated by 28.16â (11)° out of that plane. In the crystal, the mol-ecules are linked into linear chains along the [100] direction by classical inter-molecular N-Hâ¯N hydrogen bonds.
