Structural biasing elements for in-cell histone deacetylase paralog selectivity.
J Am Chem Soc
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Abstract | We use the structural dissection of two 1,3-dioxanes with in-cell histone deacetylase (HDAC) paralog selectivity to identify key elements for selective HDAC inhibitors. We demonstrate that o-aminoanilides are inactive toward HDAC6 while apparently inhibiting deacetylases that act upon histone substrates. This finding has important clinical implications for the development of HDAC inhibitor-based treatments that do not interfere with microtubule dynamics associated with HDAC6. We also show that suberoylanilide hydroxamic acid (SAHA) alone is a nonparalog-selective HDAC inhibitor and that the 1,3-dioxane diversity appended to SAHA is essential for HDAC6 paralog selectivity. |
Year of Publication | 2003
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Journal | J Am Chem Soc
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Volume | 125
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Issue | 19
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Pages | 5586-7
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Date Published | 2003 May 14
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ISSN | 0002-7863
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DOI | 10.1021/ja0341440
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PubMed ID | 12733869
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