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. © 2010 Nature America, Inc. All rights reserved. HDACs regulate diverse cellular processes by modulating protein structure and function. Lysine acetylation is reversibly mediated by HDACs and acetyl transferases, establishing a dynamic post-translational modification of broad relevance to cell signaling and cell state1. As components of chromatin-modifying enzyme complexes, HDACs target the N-terminal tails of histone proteins and thus affect chromatin conformation and gene-specific transcription1,2. Recent research has identified a significant number of nonhistone protein substrates, thereby extending the mechanisti
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