Inhibition of Zinc-Dependent Histone Deacetylases with a Chemically Triggered Electrophile

Zarko V. Boskovic; Melissa M. Kemp; Allyson M. Freedy; Vasanthi S. Viswanathan; Marius S. Pop; Jason H. Fuller; Nicole M. Martinez; Samuel O. Figueroa Lazú; Jiyoung A. Hong; Timothy A. Lewis; Daniel Calarese; James D. Love; Amedeo Vetere; Steven C. Almo; Stuart L. Schreiber; Angela N. Koehler

doi:10.1021/acschembio.6b00012

Inhibition of Zinc-Dependent Histone Deacetylases with a Chemically Triggered Electrophile

Zarko V. Boskovic, Melissa M. Kemp, Allyson M. Freedy, Vasanthi S. Viswanathan, Marius S. Pop, Jason H. Fuller, Nicole M. Martinez, Samuel O. Figueroa Lazú, Jiyoung A. Hong, Timothy A. Lewis, Daniel Calarese, James D. Love, Amedeo Vetere, Steven C. Almo, Stuart L. Schreiber, Angela N. Koehler

Biochemistry

Research output: Contribution to journal › Article › peer-review

23 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	1844-1851
Number of pages	8
Journal	ACS Chemical Biology
Volume	11
Issue number	7
DOIs	https://doi.org/10.1021/acschembio.6b00012
State	Published - Jul 15 2016

ASJC Scopus subject areas

Biochemistry
Molecular Medicine

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10.1021/acschembio.6b00012

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Boskovic, Z. V., Kemp, M. M., Freedy, A. M., Viswanathan, V. S., Pop, M. S., Fuller, J. H., Martinez, N. M., Figueroa Lazú, S. O., Hong, J. A., Lewis, T. A., Calarese, D., Love, J. D., Vetere, A., Almo, S. C., Schreiber, S. L., & Koehler, A. N. (2016). Inhibition of Zinc-Dependent Histone Deacetylases with a Chemically Triggered Electrophile. ACS Chemical Biology, 11(7), 1844-1851. https://doi.org/10.1021/acschembio.6b00012

Boskovic, ZV, Kemp, MM, Freedy, AM, Viswanathan, VS, Pop, MS, Fuller, JH, Martinez, NM, Figueroa Lazú, SO, Hong, JA, Lewis, TA, Calarese, D, Love, JD, Vetere, A, Almo, SC, Schreiber, SL & Koehler, AN 2016, 'Inhibition of Zinc-Dependent Histone Deacetylases with a Chemically Triggered Electrophile', ACS Chemical Biology, vol. 11, no. 7, pp. 1844-1851. https://doi.org/10.1021/acschembio.6b00012

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abstract = "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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AU - Pop, Marius S.

AU - Fuller, Jason H.

AU - Martinez, Nicole M.

AU - Figueroa Lazú, Samuel O.

AU - Hong, Jiyoung A.

AU - Lewis, Timothy A.

AU - Calarese, Daniel

AU - Love, James D.

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Inhibition of Zinc-Dependent Histone Deacetylases with a Chemically Triggered Electrophile

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