Fluorous-based small-molecule microarrays for the discovery of histone deacetylase inhibitors
Fluorous-based small-molecule microarrays for the discovery of histone deacetylase inhibitors
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DOI：
10.1002/anie.200703198
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发表时间：
2007-01-01
影响因子：
16.6
通讯作者：
Schreiber, Stuart L.
中科院分区：
文献类型：
--
作者：
Vegas, Arturo J.;Bradner, James E.;Schreiber, Stuart L.
可逆乙酰化在确定染色质状态和调节不同组织基因组DNA差异转录中起关键作用。[1-3]组蛋白脱乙酰基酶（HDAC）通过催化组蛋白N-末端尾部中发现的赖氨酸残基上的N-乙酰基水解在该过程中起作用。[4]该过程介导细胞分化，与表观遗传相关，并且在人类疾病中失调。[1-3鉴定新型HDAC抑制剂是日益活跃的研究领域。[6-10] Trapoxin是一种天然存在的HDAC抑制剂，在HDAC 1的最初发现中发挥了重要作用。[4]抑制HDAC酶家族多个成员的辛二酰苯胺异羟肟酸（SAHA/伏立诺他）最近已被批准用于治疗皮肤T细胞淋巴瘤。[11-13] Tubacin是第一个同源选择性抑制剂（对HDAC 6具有选择性），阐明了HDAC 6和微管蛋白乙酰化的功能。[14-19]涉及荧光读数的生化酶活性测定经常用于鉴定新的HDAC抑制剂。然而，这种方法需要昂贵的试剂和设备，并且可能难以以高通量方式进行。小分子微阵列（SMM）为HDAC抑制剂的高通量鉴定提供了一种有吸引力的选择。目前没有
Reversible acetylation plays a key role in defining chromatin states and in regulating transcription from genomic DNA differentially across distinct tissues.[1–3] Histone deacetylases (HDACs) function in this process by catalyzing the hydrolysis of N-acetyl groups on lysine residues found in the N-terminal tails of histone proteins.[4] This process mediates cell differentiation, correlates with epigenetic inheritance, and is deregulated in human disease, among others.[1–3, 5] Identifying novel HDAC inhibitors is an increasingly active area of research.[6–10] Trapoxin, which is a naturally occurring HDAC inhibitor, was instrumental in the original discovery of HDAC1.[4] Suberoylaniline hydroxamic acid (SAHA/vorinostat), which inhibits multiple members of the HDAC family of enzymes, has been approved recently for the treatment of cutaneous T-cell lymphoma.[11–13] Tubacin, which is the first homologue-selective inhibitor (having selectivity for HDAC6), has illuminated the function of HDAC6 and tubulin acetylation.[14–19]Biochemical, enzyme-activity assays involving fluorescent readouts are frequently used to identify new HDAC inhibitors. However, this approach requires expensive reagents and equipment, and can be difficult to perform in a highthroughput manner. Small-molecule microarrays (SMMs) provide an attractive alternative for high-throughput identification of HDAC inhibitors. Currently, there are no