Selective class IIa histone deacetylase inhibition via a nonchelating zinc-binding group
Top Cited Papers
- 24 March 2013
- journal article
- Published by Springer Science and Business Media LLC in Nature Chemical Biology
- Vol. 9 (5), 319-325
- https://doi.org/10.1038/nchembio.1223
Abstract
In contrast to studies on class I histone deacetylase (HDAC) inhibitors, the elucidation of the molecular mechanisms and therapeutic potential of class IIa HDACs (HDAC4, HDAC5, HDAC7 and HDAC9) is impaired by the lack of potent and selective chemical probes. Here we report the discovery of inhibitors that fill this void with an unprecedented metal-binding group, trifluoromethyloxadiazole (TFMO), which circumvents the selectivity and pharmacologic liabilities of hydroxamates. We confirm direct metal binding of the TFMO through crystallographic approaches and use chemoproteomics to demonstrate the superior selectivity of the TFMO series relative to a hydroxamate-substituted analog. We further apply these tool compounds to reveal gene regulation dependent on the catalytic active site of class IIa HDACs. The discovery of these inhibitors challenges the design process for targeting metalloenzymes through a chelating metal-binding group and suggests therapeutic potential for class IIa HDAC enzyme blockers distinct in mechanism and application compared to current HDAC inhibitors.Keywords
This publication has 34 references indexed in Scilit:
- Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic strokeNature Genetics, 2012
- SAHA Decreases HDAC 2 and 4 Levels In Vivo and Improves Molecular Phenotypes in the R6/2 Mouse Model of Huntington's DiseasePLOS ONE, 2011
- Endogenous modulators and pharmacological inhibitors of histone deacetylases in cancer therapyOncogene, 2011
- Histone Deacetylase 9 (HDAC9) Regulates the Functions of the ATDC (TRIM29) ProteinOnline Journal of Public Health Informatics, 2010
- Oncotype DX tumor gene expression profiling in stage II colon cancerApplication: Prognostic, risk predictionPLoS Currents, 2010
- Evaluation of Histone Deacetylases as Drug Targets in Huntington’s Disease modelsStudy of HDACs in brain tissues from R6/2 and CAG140 knock-in HD mouse models and human patients and in a neuronal HD cell model.PLoS Currents, 2010
- Chemical phylogenetics of histone deacetylasesNature Chemical Biology, 2010
- Structural and Functional Analysis of the Human HDAC4 Catalytic Domain Reveals a Regulatory Structural Zinc-binding DomainJournal of Biological Chemistry, 2008
- Human HDAC7 Harbors a Class IIa Histone Deacetylase-specific Zinc Binding Motif and Cryptic Deacetylase ActivityOnline Journal of Public Health Informatics, 2008
- Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylasesProceedings of the National Academy of Sciences of the United States of America, 2007