Division of Newborn Medicine and Epigenetics Program, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts 02115.
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115.
Cold Spring Harb Perspect Med. 2017 Jan 3;7(1):a026484. doi: 10.1101/cshperspect.a026484.
The dynamic regulation of covalent modifications to histones is essential for maintaining genomic integrity and cell identity and is often compromised in cancer. Aberrant expression of histone lysine demethylases has been documented in many types of blood and solid tumors, and thus demethylases represent promising therapeutic targets. Recent advances in high-throughput chemical screening, structure-based drug design, and structure-activity relationship studies have improved both the specificity and the in vivo efficacy of demethylase inhibitors. This review will briefly outline the connection between demethylases and cancer and will provide a comprehensive overview of the structure, specificity, and utility of currently available demethylase inhibitors. To date, a select group of demethylase inhibitors is being evaluated in clinical trials, and additional compounds may soon follow from the bench to the bedside.
组蛋白共价修饰的动态调控对于维持基因组完整性和细胞身份至关重要，而这种调控在癌症中经常受到破坏。许多类型的血液和实体肿瘤中都有组蛋白赖氨酸去甲基酶的异常表达，因此去甲基酶是很有前途的治疗靶点。高通量化学筛选、基于结构的药物设计和结构活性关系研究的最新进展提高了去甲基酶抑制剂的特异性和体内疗效。这篇综述将简要概述去甲基酶与癌症之间的联系，并全面概述目前可用的去甲基酶抑制剂的结构、特异性和用途。迄今为止，已有一组选择性的去甲基酶抑制剂正在临床试验中进行评估，并且可能很快会有更多的化合物从实验室走向临床。
