Abstract
Inhibition of Sonic hedgehog (Shh) signaling is of great clinical interest. Here we exploit Hedgehog acyltransferase (Hhat)-mediated Shh palmitoylation, a modification critical for Shh signaling, as a new target for Shh pathway inhibition. A target-oriented high-throughput screen was used to identify small-molecule inhibitors of Hhat. In cells, these Hhat inhibitors specifically block Shh palmitoylation and inhibit autocrine and paracrine Shh signaling.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acyltransferases / antagonists & inhibitors*
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Acyltransferases / genetics
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Acyltransferases / metabolism
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Animals
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COS Cells
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Chlorocebus aethiops
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Gene Expression / drug effects
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Genes, Reporter
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Hedgehog Proteins / antagonists & inhibitors*
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Hedgehog Proteins / genetics
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Hedgehog Proteins / metabolism
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High-Throughput Screening Assays
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Humans
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Lipoylation
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Luciferases
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Mice
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Porcupines
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Signal Transduction / drug effects*
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Small Molecule Libraries / chemistry
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Small Molecule Libraries / pharmacology*
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Structure-Activity Relationship
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Transfection
Substances
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Enzyme Inhibitors
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Hedgehog Proteins
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Small Molecule Libraries
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Luciferases
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Acyltransferases
Associated data
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PubChem-Substance/160660624
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PubChem-Substance/160660625
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PubChem-Substance/160660626
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PubChem-Substance/160660627
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PubChem-Substance/160660628
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PubChem-Substance/160660629