TY - JOUR
T1 - Chemical phylogenetics of histone deacetylases
AU - Bradner, James E.
AU - West, Nathan
AU - Grachan, Melissa L.
AU - Greenberg, Edward F.
AU - Haggarty, Stephen J.
AU - Warnow, Tandy
AU - Mazitschek, Ralph
N1 - We thank S. Schreiber and the Broad Chemical Biology Program for research space and support. We thank J. Clardy, T. Mitchison, R. Weissleder, O. Wiest, R. Williams (Colorado State University), T. Lewis (Broad Institute) and R. Maglathlin (Broad Institute) for support, thoughtful discussions and access to key instrumentation and reagents. We thank A. Stamatakis for helpful discussions on phylogenetics. We thank C. Johnson, G. Beletsky and S. Jonston for analytical support. This work was supported by grants from the US National Cancer Institute (1K08CA128972; J.E.B.), the American Society of Hematology (J.E.B.), the Multiple Myeloma Research Foundation (J.E.B.), the Burroughs-Wellcome Foundation (J.E.B.), the US National Institutes of Health (T32CA079443 to M.L.G., 1R01DA028301-01 to S.J.H. and P01CA078048 to R.M.), and the US National Science Foundation (DEB 0733029 and ITR 0331453 to T.W.). The project has been funded in part with funds from the US National Cancer Institute’s Initiative for Chemical Genetics (contract number N01-CO-12400). The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by the US government.
PY - 2010/3
Y1 - 2010/3
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/77249087051
UR - https://www.scopus.com/pages/publications/77249087051#tab=citedBy
U2 - 10.1038/nchembio.313
DO - 10.1038/nchembio.313
M3 - Article
AN - SCOPUS:77249087051
SN - 1552-4450
VL - 6
SP - 238
EP - 243
JO - Nature chemical biology
JF - Nature chemical biology
IS - 3
ER -