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 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.
[1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Chemical Biology Program, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. [3] Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
James E
JE
Bradner
Nathan
N
West
Melissa L
ML
Grachan
Edward F
EF
Greenberg
Stephen J
SJ
Haggarty
Tandy
T
Warnow
Ralph
R
Mazitschek