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Issue 3, 2014
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Acyl protein thioesterase inhibitors as probes of dynamic S-palmitoylation

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Abstract

Protein palmitoylation describes the hydrophobic post-translational modification of cysteine residues in certain proteins, and is required for the spatial organization and composition of cellular membrane environments. Certain palmitoylated proteins are processed by acyl protein thioesterase (APT) enzymes, which catalyze thioester hydrolysis of palmitoylated cysteine residues. Inhibiting APT enzymes disrupts Ras trafficking and attenuates oncogenic growth signaling, highlighting these enzymes as potential therapeutic targets. As members of the serine hydrolase enzyme family, APT enzymes can be assayed by fluorophosphonate activity-based protein profiling (ABPP) methods, allowing rapid profiling of inhibitor selectivity and potency. In this review, we discuss recent progress in the development of potent and selective inhibitors to APT enzymes, including both reversible and irreversible inhibitor chemotypes. These examples highlight how ABPP methods integrate with medicinal chemistry for the discovery and optimization of inhibitors in complex proteomes.

Graphical abstract: Acyl protein thioesterase inhibitors as probes of dynamic S-palmitoylation

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Publication details

The article was received on 30 Oct 2013, accepted on 25 Nov 2013 and first published on 02 Dec 2013


Article type: Review Article
DOI: 10.1039/C3MD00333G
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Citation: Med. Chem. Commun., 2014,5, 268-276

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    Acyl protein thioesterase inhibitors as probes of dynamic S-palmitoylation

    D. Davda and B. R. Martin, Med. Chem. Commun., 2014, 5, 268
    DOI: 10.1039/C3MD00333G

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