title: Discovery of potent, selective small molecule inhibitors of α-subtype of type III phosphatidylinositol-4-kinase (PI4KIIIα).
abstract: The discovery and optimisation of novel, potent and selective small molecule inhibitors of the α-isoform of type III phosphatidylinositol-4-kinase (PI4Kα) are described. Lead compounds show cellular activity consistent with their PI4Kα potency inhibiting the accumulation of IP1 after PDGF stimulation and reducing cellular PIP, PIP2 and PIP3 levels. Hence, these compounds are useful in vitro tools to delineate the complex biological pathways involved in signalling through PI4Kα.
authors.affiliation: AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, UK. Electronic address: piotr.raubo@astrazeneca.com.
authors.forename: Piotr
authors.initials: P
authors.lastname: Raubo
authors.affiliation: AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, UK.
authors.forename: David M
authors.initials: DM
authors.lastname: Andrews
authors.affiliation: Cancer Research Technology, London BioScience Innovation Centre, 2 Royal College Street, London NW1 0NH, UK.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: McKelvie
authors.affiliation: AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, UK.
authors.forename: Graeme R
authors.initials: GR
authors.lastname: Robb
authors.affiliation: AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, UK; Cancer Research Technology, Jonas Webb Building, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors.forename: James M
authors.initials: JM
authors.lastname: Smith
authors.affiliation: Cancer Research Technology, Jonas Webb Building, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Swarbrick
authors.affiliation: AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Waring
mesh_terms: D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D015778:Minor Histocompatibility Antigens; D008958:Models, Molecular; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007295:Inositol Phosphates; D015778:Minor Histocompatibility Antigens; D010982:Platelet-Derived Growth Factor; D054852:Small Molecule Libraries; D017853:Phosphotransferases (Alcohol Group Acceptor); C402182:phosphatidylinositol phosphate 4-kinase
keywords: IP1; In vitro tools; Oncology; PI4Kα