Department of Cell Biology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
Proc Natl Acad Sci U S A. 2013 Sep 24;110(39):15704-9. doi: 10.1073/pnas.1313893110. Epub 2013 Sep 10.
Development of isoform-selective histone deacetylase (HDAC) inhibitors is important in elucidating the function of individual HDAC enzymes and their potential as therapeutic agents. Among the eleven zinc-dependent HDACs in humans, HDAC6 is structurally and functionally unique. Here, we show that a hydroxamic acid-based small-molecule N-hydroxy-4-(2-[(2-hydroxyethyl)(phenyl)amino]-2-oxoethyl)benzamide (HPOB) selectively inhibits HDAC6 catalytic activity in vivo and in vitro. HPOB causes growth inhibition of normal and transformed cells but does not induce cell death. HPOB enhances the effectiveness of DNA-damaging anticancer drugs in transformed cells but not normal cells. HPOB does not block the ubiquitin-binding activity of HDAC6. The HDAC6-selective inhibitor HPOB has therapeutic potential in combination therapy to enhance the potency of anticancer drugs.
开发同工酶选择性组蛋白去乙酰化酶（HDAC）抑制剂对于阐明个别 HDAC 酶的功能及其作为治疗剂的潜力非常重要。在人类的 11 种锌依赖性 HDAC 中，HDAC6 在结构和功能上是独特的。在这里，我们表明基于羟肟酸的小分子 N-羟基-4-（2-[[（2-羟乙基）（苯基）氨基]-2-氧代乙基]苯甲酰胺（HPOB）在体内和体外选择性抑制 HDAC6 的催化活性。HPOB 导致正常和转化细胞的生长抑制，但不会诱导细胞死亡。HPOB 增强了转化细胞中 DNA 损伤抗癌药物的有效性，但对正常细胞没有影响。HPOB 不阻断 HDAC6 的泛素结合活性。HDAC6 选择性抑制剂 HPOB 在联合治疗中具有增强抗癌药物效力的治疗潜力。
