Chemical Phylogenetics of Histone Deacetylases
By James E. Bradner, N. West, Melissa L. Grachan, Edward F. Greenberg, S. Haggarty, Tandy J. Warnow, Ralph Mazitschek. Nature Chemical Biology, 2010
702 citations recorded by the source corpus.
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.
Subfields: Molecular Biology, Organic Chemistry
View Paper: https://www.semanticscholar.org/paper/68c4985bcae290a761e64065e7e4cfe062700c7f
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Citations in the corpus
- Pathophysiology of cardiac hypertrophy and heart failure: signaling pathways and novel therapeutic targets (2015, background): “Compared with class I HDACs (HDAC1, 2, 3 and 8) and class IIb HDACs (HDAC6 and 10), class IIa HDACs (HDAC4, HDAC5, HDAC7 and HDAC9) have very low enzymatic activity (Bradner et al. 2010; Lahm et al. 2007) and repress gene transcription primarily via protein–protein interactions with transcription fa”
- Erasers of histone acetylation: the histone deacetylase enzymes. (2014, background): “The sensitivity to these inhibitors varies widely Cite this article as Cold Spring Harb Perspect Biol 2014;6:a018713 19 among different HDACs, with some HDAC activities inhibited only above pharmacologically relevant concentrations (Bradner et al. 2010).”
- New and emerging HDAC inhibitors for cancer treatment. (2014, positive): “remains a further challenge, but the development of the HDAC chemical phylogenetic tree (35) and identification of specific substrates of individual HDACs, such as SMC3 for HDAC8 (36), may”
- Lysine Glutarylation Is a Protein Post-Translational Modification Regulated by SIRT5 (2014, background): “…substrates containing 7-amino-4-methylcoumarin (AMC) were evaluated: one series based on a simple a-N-acetylated lysine (Figure 4A) and one containing the tripeptide sequence, Ac-Leu-Gly-Lys(acyl), which is based on H4K12—a common substrate for deacylation (Bradner et al., 2010) (Figure S4A).”
- A Next Generation Connectivity Map: L1000 platform and the first 1,000,000 profiles (2017, background): “The pan-HDAC inhibitors generally cluster together, distinct from the more isoform-selective compounds, suggesting that gene expression can be used to further stratify compounds within the same class (Fass et al. 2010; Bradner et al. 2010; Butler et al. 2010; Kwon et al. 1998; Arts et al. 2009; Hagg”
- Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes (2011, background): “Class IIa HDACs exhibit low enzymatic activity and are proposed to have “modification reader” or scaffold function”