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J Lipid Res. 2019 Mar;60(3):683-693. doi: 10.1194/jlr.D090159. Epub 2019 Jan 9.

A large scale high-throughput screen identifies chemical inhibitors of phosphatidylinositol 4-kinase type II alpha.

Author information

1
Section on Molecular Signal Transduction, Program for Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.
2
Division of Preclinical Innovation National Center for Advancing Translational Sciences, Rockville, MD 20850.
3
Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic, 166 10 Prague 6, Czech Republic.
4
Section on Molecular Signal Transduction, Program for Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892 ballat@mail.nih.gov.

Abstract

The minor phospholipid, phosphatidylinositol 4-phosphate (PI4P), is emerging as a key regulator of lipid transfer in ER-membrane contact sites. Four different phosphatidylinositol 4-kinase (PI4K) enzymes generate PI4P in different membrane compartments supporting distinct cellular processes, many of which are crucial for the maintenance of cellular integrity but also hijacked by intracellular pathogens. While type III PI4Ks have been targeted by small molecular inhibitors, thus helping decipher their importance in cellular physiology, no inhibitors are available for the type II PI4Ks, which hinders investigations into their cellular functions. Here, we describe the identification of small molecular inhibitors of PI4K type II alpha (PI4K2A) by implementing a large scale small molecule high-throughput screening. A novel assay was developed that allows testing of selected inhibitors against PI4K2A in intact cells using a bioluminescence resonance energy transfer approach adapted to plate readers. The compounds disclosed here will pave the way to the optimization of PI4K2A inhibitors that can be used in cellular and animal studies to better understand the role of this enzyme in both normal and pathological states.

KEYWORDS:

endosome; phosphoinositide; vesicular traffic

PMID:
30626625
PMCID:
PMC6399489
[Available on 2020-03-01]
DOI:
10.1194/jlr.D090159

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