title: DW09849, a selective phosphatidylinositol 3-kinase (PI3K) inhibitor, prevents PI3K signaling and preferentially inhibits proliferation of cells containing the oncogenic mutation p110α (H1047R).
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.
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research (J.-l.L., X.Z., C.-l.G., X.W., L-j.T., J.D., L-h.M.) and Department of Medicinal Chemistry (W-h.D.), Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China; and School of Pharmacy, East China University of Science and Technology, Shanghai, P.R. China (G.-r.G., S.-f.C. W.-h.D.).
authors.forename: Jia-li
authors.initials: JL
authors.lastname: Liu
authors.forename: Guo-rui
authors.initials: GR
authors.lastname: Gao
authors.forename: Xi
authors.initials: X
authors.lastname: Zhang
authors.forename: Su-fen
authors.initials: SF
authors.lastname: Cao
authors.forename: Chen-liang
authors.initials: CL
authors.lastname: Guo
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.forename: Lin-jiang
authors.initials: LJ
authors.lastname: Tong
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.forename: Wen-hu
authors.initials: WH
authors.lastname: Duan
authors.forename: Ling-hua
authors.initials: LH
authors.lastname: Meng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D059585:G1 Phase Cell Cycle Checkpoints; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D009154:Mutation; D009857:Oncogenes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D006574:Heterocyclic Compounds, 2-Ring; D006835:Hydrazones; C587453:N'-((6-bromoimidazo(1,2-a)pyridin-3-yl)methylene)-N-ethyl-2-methyl-5-nitrobenzohydrazide; D000081082:Phosphoinositide-3 Kinase Inhibitors; D058543:Class Ia Phosphatidylinositol 3-Kinase; D058570:TOR Serine-Threonine Kinases