title: Potent, selective small molecule inhibitors of type III phosphatidylinositol-4-kinase α- but not β-inhibit the phosphatidylinositol signaling cascade and cancer cell proliferation.
abstract: Two series of inhibitors of type III phosphatidylinositol-4-kinase were identified by high throughput screening and optimised to derive probe compounds that independently and selectively inhibit the α- and the β-isoforms with no significant activity towards related kinases in the pathway. In a cellular environment, inhibition of the α- but not the β-subtype led to a reduction in phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5-bisphosphate concentration, causing inhibition of inositol-1-phosphate formation and inhibition of proliferation in a panel of cancer cell lines.
authors.affiliation: AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. mike.j.waring@astrazeneca.com.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Waring
authors.forename: David M
authors.initials: DM
authors.lastname: Andrews
authors.forename: Paul F
authors.initials: PF
authors.lastname: Faulder
authors.forename: Vikki
authors.initials: V
authors.lastname: Flemington
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: McKelvie
authors.forename: Sarita
authors.initials: S
authors.lastname: Maman
authors.forename: Marian
authors.initials: M
authors.lastname: Preston
authors.forename: Piotr
authors.initials: P
authors.lastname: Raubo
authors.forename: Graeme R
authors.initials: GR
authors.lastname: Robb
authors.forename: Karen
authors.initials: K
authors.lastname: Roberts
authors.forename: Rachel
authors.initials: R
authors.lastname: Rowlinson
authors.forename: James M
authors.initials: JM
authors.lastname: Smith
authors.forename: Martin E
authors.initials: ME
authors.lastname: Swarbrick
authors.forename: Iris
authors.initials: I
authors.lastname: Treinies
authors.forename: Jon J G
authors.initials: JJ
authors.lastname: Winter
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wood
mesh_terms: D019870:1-Phosphatidylinositol 4-Kinase / Q000037:antagonists & inhibitors*; D049109:Cell Proliferation / Q000187:drug effects; D057166:High-Throughput Screening Assays; D006801:Humans; D007295:Inositol Phosphates / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D007295:Inositol Phosphates; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; C037178:phosphatidylinositol 4-phosphate; C002647:inositol 1-phosphate; D019870:1-Phosphatidylinositol 4-Kinase