Bradner James E, West Nathan, Grachan Melissa L, Greenberg Edward F, Haggarty Stephen J, Warnow Tandy, Mazitschek Ralph
[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.
Nat Chem Biol. 2010 Mar;6(3):238-243. doi: 10.1038/nchembio.313. Epub 2010 Feb 7.
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.
在化学、生物学和医学领域对组蛋白去乙酰化酶进行广泛研究依赖于工具化合物来获得机理上的见解。对作为一组全面的、结构多样的抑制剂靶点的I类和II类组蛋白去乙酰化酶（HDAC）进行系统发育分析，结果显示，即使在被广泛认为是非选择性的化合物中，也存在意想不到的亚型选择性。对肉桂酸异羟肟酸聚焦文库的合成和研究使我们鉴定出了据我们所知的首个非选择性HDAC抑制剂。这些数据将指导更明智地使用HDAC抑制剂作为化学探针和治疗剂。
