Inhibition of Zinc-Dependent Histone Deacetylases with a Chemically Triggered Electrophile
Unbiased binding assays involving small-molecule microarrays were used to identify compounds that display unique patterns of selectivity among members of the zinc-dependent histone deacetylase family of enzymes. A novel, hydroxyquinoline-containing compound, BRD4354, was shown to preferentially inhibit activity of HDAC5 and HDAC9 in vitro. Inhibition of deacetylase activity appears to be time-dependent and reversible. Mechanistic studies suggest that the compound undergoes zinc-catalyzed decomposition to an ortho-quinone methide, which covalently modifies nucleophilic cysteines within the proteins. The covalent nature of the compound-enzyme interaction has been demonstrated in experiments with biotinylated probe compound and with electrospray ionization-mass spectrometry..
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2016 |
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| Erschienen: |
2016 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
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| Enthalten in: |
ACS chemical biology - 11(2016), 7, Seite 1844 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Boskovic, Zarko V [VerfasserIn] |
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| 520 | |a Unbiased binding assays involving small-molecule microarrays were used to identify compounds that display unique patterns of selectivity among members of the zinc-dependent histone deacetylase family of enzymes. A novel, hydroxyquinoline-containing compound, BRD4354, was shown to preferentially inhibit activity of HDAC5 and HDAC9 in vitro. Inhibition of deacetylase activity appears to be time-dependent and reversible. Mechanistic studies suggest that the compound undergoes zinc-catalyzed decomposition to an ortho-quinone methide, which covalently modifies nucleophilic cysteines within the proteins. The covalent nature of the compound-enzyme interaction has been demonstrated in experiments with biotinylated probe compound and with electrospray ionization-mass spectrometry. | ||
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| 700 | 1 | |a Pop, Marius S |4 oth | |
| 700 | 1 | |a Fuller, Jason H |4 oth | |
| 700 | 1 | |a Martinez, Nicole M |4 oth | |
| 700 | 1 | |a Figueroa Lazú, Samuel O |4 oth | |
| 700 | 1 | |a Hong, Jiyoung A |4 oth | |
| 700 | 1 | |a Lewis, Timothy A |4 oth | |
| 700 | 1 | |a Calarese, Daniel |4 oth | |
| 700 | 1 | |a Love, James D |4 oth | |
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