Article | Published:

Chemical phylogenetics of histone deacetylases

Nature Chemical Biology volume 6, pages 238243 (2010) | Download Citation

Abstract

The broad study of histone deacetylases in chemistry, biology and medicine relies on tool compounds to derive mechanistic insights. A phylogenetic analysis of class I and II histone deacetylases (HDACs) as targets of a comprehensive, structurally diverse panel of inhibitors revealed unexpected isoform selectivity even among compounds widely perceived as nonselective. The synthesis and study of a focused library of cinnamic hydroxamates allowed the identification of, to our knowledge, the first nonselective HDAC inhibitor. These data will guide a more informed use of HDAC inhibitors as chemical probes and therapeutic agents.

  • Compound C14H20N2O3

    Suberoylanilide hydroxamic acid

  • Compound C24H36N4O6S2

    FK-228

  • Compound C28H39N5O7

    (S)-6-Acetamido-2-(2-((S)-2-acetamido-4-methylpentanamido)acetamido)-N-(4-methyl-2-oxo-2H-chromen-7-yl)hexanamide

  • Compound C23H28F3N3O6

    (S)-tert-Butyl (1-((4-methyl-2-oxo-2H-chromen-7-yl)amino)-1-oxo-6-(2,2,2-trifluoroacetamido)hexan-2-yl)carbamate

  • Compound C23H31N3O6

    (S)-tert-Butyl (6-acetamido-1-((4-methyl-2-oxo-2H-chromen-7-yl)amino)-1-oxohexan-2-yl)carbamate

  • Compound C28H36F3N5O7

    (S)-2-(2-((S)-2-Acetamido-4-methylpentanamido)acetamido)-N-(4-methyl-2-oxo-2H-chromen-7-yl)-6-(2,2,2-trifluoroacetamido)hexanamide

  • Compound C34H51N5O6

    Apicidin

  • Compound C17H22N2O3

    Trichostatin A

  • Compound C24H27N3O4

    ITF-2357

  • Compound C15H14N2O4S

    PXD-101

  • Compound C21H23N3O2

    LBH-589

  • Compound C22H25N3O3

    LAQ-824

  • Compound C13H19N3O3

    Pyroxamide

  • Compound C18H18N2O4

    Scriptaid

  • Compound C41H43N3O7S

    Tubacin

  • Compound C8H16N2O4

    Suberohydroxamic acid

  • Compound C16H16N2O3

    3-(4-Aroyl-1-methyl-1H-pyrrol-2-yl)-N-hydroxy-2-propenamide

  • Compound C23H20N6O

    MGCD-0103

  • Compound C21H20N4O3

    MS-275

  • Compound C15H15N3O2

    CI-994

  • Compound C26H29N3O6

    (S)-Benzyl (6-acetamido-1-((4-methyl-2-oxo-2H-chromen-7-yl)amino)-1-oxohexan-2-yl)carbamate

  • Compound C17H15N3O6

    Pandacostat

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Acknowledgements

We thank S. Schreiber and the Broad Chemical Biology Program for research space and support. We thank J. Clardy, T. Mitchison, R. Weissleder, O. Wiest, R. Williams (Colorado State University), T. Lewis (Broad Institute) and R. Maglathlin (Broad Institute) for support, thoughtful discussions and access to key instrumentation and reagents. We thank A. Stamatakis for helpful discussions on phylogenetics. We thank C. Johnson, G. Beletsky and S. Jonston for analytical support. This work was supported by grants from the US National Cancer Institute (1K08CA128972; J.E.B.), the American Society of Hematology (J.E.B.), the Multiple Myeloma Research Foundation (J.E.B.), the Burroughs-Wellcome Foundation (J.E.B.), the US National Institutes of Health (T32CA079443 to M.L.G., 1R01DA028301-01 to S.J.H. and P01CA078048 to R.M.), and the US National Science Foundation (DEB 0733029 and ITR 0331453 to T.W.). The project has been funded in part with funds from the US National Cancer Institute's Initiative for Chemical Genetics (contract number N01-CO-12400). The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the US government.

Author information

Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • James E Bradner
    • , Nathan West
    •  & Edward F Greenberg
  2. Chemical Biology Program, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • James E Bradner
    • , Nathan West
    • , Edward F Greenberg
    • , Stephen J Haggarty
    •  & Ralph Mazitschek
  3. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

    • James E Bradner
  4. Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Melissa L Grachan
    •  & Ralph Mazitschek
  5. Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Stephen J Haggarty
  6. Department of Computer Sciences, University of Texas, Austin, Texas, USA.

    • Tandy Warnow
  7. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.

    • Ralph Mazitschek

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Contributions

J.E.B. developed biochemical methods, analyzed data, designed and synthesized the cinnamic hydroxmate library, provided research funding, supervised, prepared the manuscript and mentored N.W., M.L.G. and E.F.G. N.W. developed the class IIa biochemical methods, analyzed data and synthesized pandacostat. M.L.G. synthesized and purified pandacostat and analyzed data. E.F.G. developed the class I and IIb biochemical methods and analyzed data. S.J.H. designed experiments and provided reagents. T.W. advised on phylogenetic analysis. R.M. designed and synthesized substrates and tool HDAC inhibitors, synthesized the cinnamic hydroxmate library, developed methods, analyzed data, provided research funding, prepared the manuscript, and mentored M.L.G. The corresponding authors (J.E.B. and R.M.) certify that all authors have agreed to all the content in the manuscript, including the data as presented.

Competing interests

J.E.B. and R.M. are scientific founders of and shareholders in SHAPE Pharmaceuticals and Acetylon Pharmaceuticals.

Corresponding authors

Correspondence to James E Bradner or Ralph Mazitschek.

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    Supplementary Text and Figures

    Supplementary Methods, Supplementary Figures 1–8 and Supplementary Table 1

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DOI

https://doi.org/10.1038/nchembio.313

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