School of Chemistry and Biochemistry, Georgia Institute of Technology , Atlanta, Georgia 30332-0400, United States.
J Med Chem. 2013 May 9;56(9):3492-506. doi: 10.1021/jm301769u. Epub 2013 Apr 18.
Small molecules bearing hydroxamic acid as the zinc binding group (ZBG) have been the most effective histone deacetylase inhibitors (HDACi) to date. However, concerns about the pharmacokinetic liabilities of the hydroxamic acid moiety have stimulated research efforts aimed at finding alternative nonhydroxamate ZBGs. We have identified 3-hydroxypyridin-2-thione (3-HPT) as a novel ZBG that is compatible with HDAC inhibition. 3-HPT inhibits HDAC 6 and HDAC 8 with an IC50 of 681 and 3675 nM, respectively. Remarkably, 3-HPT gives no inhibition of HDAC 1. Subsequent optimization led to several novel 3HPT-based HDACi that are selective for HDAC 6 and HDAC 8. Furthermore, a subset of these inhibitors induces apoptosis in various cancer cell lines.
小分子作为锌结合基团（ZBG）的羟肟酸一直是最有效的组蛋白去乙酰化酶抑制剂（HDACi）。然而，人们对羟肟酸部分的药代动力学缺陷的担忧，激发了旨在寻找替代非羟肟酸 ZBG 的研究工作。我们已经确定 3-羟基吡啶-2-硫酮（3-HPT）为新型 ZBG，与 HDAC 抑制兼容。3-HPT 对 HDAC6 和 HDAC8 的抑制作用的 IC50 分别为 681 和 3675 nM。值得注意的是，3-HPT 对 HDAC1 没有抑制作用。随后的优化导致了几种新型基于 3-HPT 的 HDACi，它们对 HDAC6 和 HDAC8 具有选择性。此外，这些抑制剂中的一部分能诱导各种癌细胞系凋亡。
