Chemical Phylogenetics of Histone Deacetylases

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 HDACs as targets of a comprehensive, structurally diverse panel of inhibitors revealed unexpected isoform selectivity even among compounds widely perceived as non-selective. The synthesis and study of a focused library of cinnamic hydroxamates allowed the identification of a first non-selective HDAC inhibitor. These data will guide a more informed use of HDAC inhibitors as chemical probes and therapeutic agents.

[1]  Guoping Feng,et al.  The Histone Deacetylase HDAC4 Connects Neural Activity to Muscle Transcriptional Reprogramming* , 2007, Journal of Biological Chemistry.

[2]  Kazutaka Katoh,et al.  Recent developments in the MAFFT multiple sequence alignment program , 2008, Briefings Bioinform..

[3]  R. De Francesco,et al.  Probing the elusive catalytic activity of vertebrate class IIa histone deacetylases. , 2008, Bioorganic & medicinal chemistry letters.

[4]  D. Mottet,et al.  Histone Deacetylase 7 Silencing Alters Endothelial Cell Migration, a Key Step in Angiogenesis , 2007, Circulation research.

[5]  D. Wegener,et al.  Improved fluorogenic histone deacetylase assay for high-throughput-screening applications. , 2003, Analytical biochemistry.

[6]  S. Mujtaba,et al.  Structure and acetyl-lysine recognition of the bromodomain , 2007, Oncogene.

[7]  Jessica E. Bolden,et al.  Anticancer activities of histone deacetylase inhibitors , 2006, Nature Reviews Drug Discovery.

[8]  S. Schreiber,et al.  Modular synthesis and preliminary biological evaluation of stereochemically diverse 1,3-dioxanes. , 2004, Chemistry & biology.

[9]  E. Olson,et al.  Protein Kinase D1 Phosphorylates HDAC7 and Induces Its Nuclear Export after T-cell Receptor Activation* , 2005, Journal of Biological Chemistry.

[10]  K. Katoh,et al.  MAFFT version 5: improvement in accuracy of multiple sequence alignment , 2005, Nucleic acids research.

[11]  R. Ficner,et al.  Crystal structure of a bacterial class 2 histone deacetylase homologue. , 2005, Journal of molecular biology.

[12]  O. Wiest,et al.  Zinc binding in HDAC inhibitors: a DFT study. , 2007, The Journal of organic chemistry.

[13]  J. Min,et al.  Human HDAC7 Harbors a Class IIa Histone Deacetylase-specific Zinc Binding Motif and Cryptic Deacetylase Activity* , 2008, Journal of Biological Chemistry.

[14]  S. Schreiber,et al.  Total synthesis and biological mode of action of largazole: a potent class I histone deacetylase inhibitor. , 2008, Journal of the American Chemical Society.

[15]  M. Mann,et al.  Lysine Acetylation Targets Protein Complexes and Co-Regulates Major Cellular Functions , 2009, Science.

[16]  P. Marks,et al.  Identification of a transcriptional repressor related to the noncatalytic domain of histone deacetylases 4 and 5. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[17]  J. Rougemont,et al.  A rapid bootstrap algorithm for the RAxML Web servers. , 2008, Systematic biology.

[18]  S. Minucci,et al.  Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer , 2006, Nature Reviews Cancer.

[19]  Tandy J. Warnow,et al.  The Impact of Multiple Protein Sequence Alignment on Phylogenetic Estimation , 2011, IEEE/ACM Transactions on Computational Biology and Bioinformatics.

[20]  Identification and Characterization of Small Molecule Inhibitors of a Class I Histone Deacetylase from Plasmodium falciparum , 2009, Journal of medicinal chemistry.

[21]  K. Katoh,et al.  MAFFT: a novel method for rapid multiple sequence alignment based on fast Fourier transform. , 2002, Nucleic acids research.

[22]  U. Koch,et al.  Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases , 2007, Proceedings of the National Academy of Sciences.

[23]  T. Yao,et al.  Intracellular Trafficking of Histone Deacetylase 4 Regulates Neuronal Cell Death , 2005, The Journal of Neuroscience.

[24]  M. Bottomley,et al.  Structural and Functional Analysis of the Human HDAC4 Catalytic Domain Reveals a Regulatory Structural Zinc-binding Domain* , 2008, Journal of Biological Chemistry.

[25]  S. Schreiber,et al.  Synthesis of 7200 small molecules based on a substructural analysis of the histone deacetylase inhibitors trichostatin and trapoxin. , 2001, Organic letters.

[26]  S. Schreiber,et al.  Synthesis and conformation-activity relationships of the peptide isosteres of FK228 and largazole. , 2009, Journal of the American Chemical Society.

[27]  E. Nestler,et al.  Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action , 2006, Nature Neuroscience.

[28]  Andreas Schwienhorst,et al.  Members of the histone deacetylase superfamily differ in substrate specificity towards small synthetic substrates. , 2004, Biochemical and biophysical research communications.

[29]  Jerry L. Workman,et al.  Histone acetyltransferase complexes: one size doesn't fit all , 2007, Nature Reviews Molecular Cell Biology.

[30]  Ivan V. Gregoretti,et al.  Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. , 2004, Journal of molecular biology.

[31]  Brian C. Smith,et al.  Mechanisms and molecular probes of sirtuins. , 2008, Chemistry & biology.

[32]  Fluorous-based small-molecule microarrays for the discovery of histone deacetylase inhibitors. , 2007, Angewandte Chemie.

[33]  J. R. Somoza,et al.  Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases. , 2004, Structure.

[34]  Guanghua Xiao,et al.  Histone Deacetylase 5 Epigenetically Controls Behavioral Adaptations to Chronic Emotional Stimuli , 2007, Neuron.