Histone acetyltransferase inhibitors

Published by wjsullivan on 1 December 2006 - 8:30pm


Request for Help

Histone acetyltransferases (HATs) and HAT inhibitors
The significance of studying HATs is underscored by an abundance of genetic studies that implicate them in having a role in disease (for reviews, see (10), (6), and (16)).  Consistent with this, some histone deacetylase (HDAC) inhibitors display anti-tumor activity and are being evaluated in clinical trials (8).  In addition to regulating transcription, HATs have crucial functions in modulating other DNA processes (7).  Histone acetylation machinery may also be a viable target for novel anti-infectives (5).
The impact of the various HATs on cellular physiology and disease would greatly benefit from the identification of specific pharmacological inhibitors, but very few have been described to date (11).  Two natural products, anacardic acid and garcinol (a polyprenylated benzophenone), are reported to inhibit both p300/CBP and PCAF in a 5-10 mM range in vitro (1, 2).  In contrast, curcumin displays activity against p300/CBP, but not PCAF (3).  Subsequent studies suggest that anacardic acid may be a broad-spectrum HAT inhibitor, as it also interferes with the MYST HAT Tip60 (13).  Isothiazolones were identified in a high-throughput screen as inhibitors of PCAF and p300 (12), but like the aforementioned compounds, activity against GCN5 was not determined.  Moreover, isothiazolones are strongly reactive with thiol groups and hence are likely to have substantial nonspecific effects.  Two small molecule inhibitors of GCN5 that have been documented include a butyrolactone (4) and MC1626 (2-methyl-3-carbethoxyquinoline) (9).  However, in our hands, the butyrolactone and MC1626 exhibit no inhibition of recombinant yeast GCN5 in a standard in vitro HAT assay (Sullivan, unpublished).  As a positive control, parallel HAT assays showed anacardic acid does inhibit yeast GCN5.
Two reports describe systems that can be used in high-throughput format to identify potential HAT inhibitors (14, 15).
We are interested in acquiring HAT inhibitors, especially those that appear to be selective for distinct types of HATs (i.e. GCN5, MYST).  Not only would these serve as valuable probes to study histone acetylation in eukaryotic cells, they may also hold promise as novel drugs to combat parasitic disease.


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2.         Balasubramanyam, K., V. Swaminathan, A. Ranganathan, and T. K. Kundu. 2003. Small molecule modulators of histone acetyltransferase p300. J Biol Chem 278:19134-40.

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12.       Stimson, L., M. G. Rowlands, Y. M. Newbatt, N. F. Smith, F. I. Raynaud, P. Rogers, V. Bavetsias, S. Gorsuch, M. Jarman, A. Bannister, T. Kouzarides, E. McDonald, P. Workman, and G. W. Aherne. 2005. Isothiazolones as inhibitors of PCAF and p300 histone acetyltransferase activity. Mol Cancer Ther 4:1521-32.

13.       Sun, Y., X. Jiang, S. Chen, and B. D. Price. 2006. Inhibition of histone acetyltransferase activity by anacardic acid sensitizes tumor cells to ionizing radiation. FEBS Lett 580:4353-6.

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