Wong Jason C, Hong Roger, Schreiber Stuart L
Department of Chemistry and Chemical Biology, Harvard Institute of Chemistry and Cell Biology, and the Howard Hughes Medical Institute, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.
J Am Chem Soc. 2003 May 14;125(19):5586-7. doi: 10.1021/ja0341440.
We use the structural dissection of two 1,3-dioxanes with in-cell histone deacetylase (HDAC) paralog selectivity to identify key elements for selective HDAC inhibitors. We demonstrate that o-aminoanilides are inactive toward HDAC6 while apparently inhibiting deacetylases that act upon histone substrates. This finding has important clinical implications for the development of HDAC inhibitor-based treatments that do not interfere with microtubule dynamics associated with HDAC6. We also show that suberoylanilide hydroxamic acid (SAHA) alone is a nonparalog-selective HDAC inhibitor and that the 1,3-dioxane diversity appended to SAHA is essential for HDAC6 paralog selectivity.
我们利用两种1,3 - 二氧六环的结构剖析以及细胞内组蛋白去乙酰化酶（HDAC）旁系同源物选择性，来确定选择性HDAC抑制剂的关键要素。我们证明邻氨基苯甲酰胺对HDAC6无活性，同时却能明显抑制作用于组蛋白底物的去乙酰化酶。这一发现对于开发不干扰与HDAC6相关微管动力学的基于HDAC抑制剂的治疗方法具有重要的临床意义。我们还表明，单独的辛二酰苯胺异羟肟酸（SAHA）是一种非旁系同源物选择性的HDAC抑制剂，而连接到SAHA上的1,3 - 二氧六环多样性对于HDAC6旁系同源物选择性至关重要。
