Discovery of potent, selective small molecule inhibitors of α-subtype of type III phosphatidylinositol-4-kinase (PI4KIIIα)

Piotr Raubo; David M Andrews; Jennifer C McKelvie; Graeme R Robb; James M Smith; Martin E Swarbrick; Michael J Waring

doi:10.1016/j.bmcl.2015.05.093

Discovery of potent, selective small molecule inhibitors of α-subtype of type III phosphatidylinositol-4-kinase (PI4KIIIα)

Bioorg Med Chem Lett. 2015 Aug 15;25(16):3189-93. doi: 10.1016/j.bmcl.2015.05.093. Epub 2015 Jun 4.

Authors

Piotr Raubo¹, David M Andrews², Jennifer C McKelvie³, Graeme R Robb², James M Smith⁴, Martin E Swarbrick⁵, Michael J Waring²

Affiliations

¹ AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, UK. Electronic address: [email protected].
² AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, UK.
³ Cancer Research Technology, London BioScience Innovation Centre, 2 Royal College Street, London NW1 0NH, UK.
⁴ AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, UK; Cancer Research Technology, Jonas Webb Building, Babraham Research Campus, Cambridge CB22 3AT, UK.
⁵ Cancer Research Technology, Jonas Webb Building, Babraham Research Campus, Cambridge CB22 3AT, UK.

PMID: 26087940
DOI: 10.1016/j.bmcl.2015.05.093

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.

Keywords: IP1; In vitro tools; Oncology; PI4Kα.

MeSH terms

Drug Design
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology*
High-Throughput Screening Assays
Humans
Inositol Phosphates / metabolism
Minor Histocompatibility Antigens
Models, Molecular
Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
Platelet-Derived Growth Factor / pharmacology
Signal Transduction / drug effects
Small Molecule Libraries
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Inositol Phosphates
Minor Histocompatibility Antigens
Platelet-Derived Growth Factor
Small Molecule Libraries
Phosphotransferases (Alcohol Group Acceptor)
phosphatidylinositol phosphate 4-kinase