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.
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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.
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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.
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J.E.B. and R.M. are scientific founders of and shareholders in SHAPE Pharmaceuticals and Acetylon Pharmaceuticals.
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Supplementary Methods, Supplementary Figures 1–8 and Supplementary Table 1 (PDF 3935 kb)
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Bradner, J., West, N., Grachan, M. et al. Chemical phylogenetics of histone deacetylases. Nat Chem Biol 6, 238–243 (2010). https://doi.org/10.1038/nchembio.313
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DOI: https://doi.org/10.1038/nchembio.313
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