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Nat Chem Biol. 2014 Jan;10(1):76-84. doi: 10.1038/nchembio.1389. Epub 2013 Nov 24.

PITPs as targets for selectively interfering with phosphoinositide signaling in cells.

Author information

1
1] Department of Molecular and Cellular Medicine, Texas A&M University College Station, Texas, USA. [2] Department of Biochemistry and Biophysics, Texas A&M University College Station, Texas, USA. [3] Department of Chemistry, Texas A&M University College Station, Texas, USA. [4] Department of Cell and Developmental Biology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
2
1] Department of Molecular and Cellular Medicine, Texas A&M University College Station, Texas, USA. [2] Department of Biochemistry and Biophysics, Texas A&M University College Station, Texas, USA. [3] Department of Chemistry, Texas A&M University College Station, Texas, USA. [4] Laboratory for Molecular Modeling, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
3
1] Department of Molecular and Cellular Medicine, Texas A&M University College Station, Texas, USA. [2] Department of Biochemistry and Biophysics, Texas A&M University College Station, Texas, USA. [3] Department of Chemistry, Texas A&M University College Station, Texas, USA.
4
Department of Biochemistry, Stanford Genome Technology Center, Stanford University, Palo Alto, California, USA.
5
Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.
6
Department of Cell and Developmental Biology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
7
Laboratory for Molecular Modeling, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
8
R.L. Juliano Structural Bioinformatics Core University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
9
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.

Abstract

Sec14-like phosphatidylinositol transfer proteins (PITPs) integrate diverse territories of intracellular lipid metabolism with stimulated phosphatidylinositol-4-phosphate production and are discriminating portals for interrogating phosphoinositide signaling. Yet, neither Sec14-like PITPs nor PITPs in general have been exploited as targets for chemical inhibition for such purposes. Herein, we validate what is to our knowledge the first small-molecule inhibitors (SMIs) of the yeast PITP Sec14. These SMIs are nitrophenyl(4-(2-methoxyphenyl)piperazin-1-yl)methanones (NPPMs) and are effective inhibitors in vitro and in vivo. We further establish that Sec14 is the sole essential NPPM target in yeast and that NPPMs exhibit exquisite targeting specificities for Sec14 (relative to related Sec14-like PITPs), propose a mechanism for how NPPMs exert their inhibitory effects and demonstrate that NPPMs exhibit exquisite pathway selectivity in inhibiting phosphoinositide signaling in cells. These data deliver proof of concept that PITP-directed SMIs offer new and generally applicable avenues for intervening with phosphoinositide signaling pathways with selectivities superior to those afforded by contemporary lipid kinase-directed strategies.

PMID:
24292071
PMCID:
PMC4059020
DOI:
10.1038/nchembio.1389
[Indexed for MEDLINE]
Free PMC Article

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