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Related Experiment Videos

Structural biasing elements for in-cell histone deacetylase paralog selectivity.

Jason C Wong1, Roger Hong, Stuart L Schreiber

  • 1Department of Chemistry and Chemical Biology, Harvard Institute of Chemistry and Cell Biology, and the Howard Hughes Medical Institute, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.

Journal of the American Chemical Society
|May 8, 2003
PubMed
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Selective histone deacetylase (HDAC) inhibitors are crucial for cancer therapy. This study identifies key structural elements for HDAC6 paralog selectivity, offering insights into developing targeted HDAC inhibitor treatments without side effects.

Area of Science:

  • Medicinal Chemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Histone deacetylase (HDAC) inhibitors are a promising class of anticancer agents.
  • HDAC6 plays a critical role in microtubule dynamics and cellular functions.
  • Developing paralog-selective HDAC inhibitors is essential to minimize off-target effects.

Purpose of the Study:

  • To identify key structural determinants for achieving in-cell histone deacetylase (HDAC) paralog selectivity.
  • To evaluate the selectivity profile of o-aminoanilides and suberoylanilide hydroxamic acid (SAHA) derivatives.
  • To guide the development of novel HDAC inhibitors with improved therapeutic potential.

Main Methods:

  • Structural dissection of two 1,3-dioxane compounds.
  • In-cell assays to assess HDAC paralog inhibition.

Related Experiment Videos

  • Evaluation of o-aminoanilides and SAHA derivatives for HDAC selectivity.

    • Main Results:

    • O-aminoanilides were found to be inactive against HDAC6 but inhibited other histone deacetylases.
    • SAHA alone demonstrated nonparalog-selective HDAC inhibition.
    • 1,3-dioxane modifications appended to SAHA were critical for achieving HDAC6 paralog selectivity.

    Conclusions:

    • The structural features of 1,3-dioxanes are key to achieving HDAC6 paralog selectivity.
    • Developing selective HDAC inhibitors, like those targeting HDAC6, can lead to improved cancer therapies with fewer side effects.
    • Findings have significant clinical implications for designing targeted HDAC inhibitor treatments.