使用α-环辛烯大唑硫醇探针进行细胞内HDAC1/2药物占有率的定量测量。
Quantitative measurement of intracellular HDAC1/2 drug occupancy using a -cyclooctene largazole thiol probe.
作者信息
Xu Hua, Roberts Lee R, Chou Song, Pierce Betsy, Narayanan Arjun, Jones Lyn H
机构信息
Pfizer Inc. Medicine Design , 610 Main Street , Cambridge , MA 02135 , USA . Email:
Pfizer Inc. Rare Diseases Research Unit , 610 Main Street , Cambridge , MA 02135 , USA.
出版信息
Medchemcomm. 2017 Jan 9;8(4):767-770. doi: 10.1039/c6md00633g. eCollection 2017 Apr 1.
Abstract
Histone deacetylases (HDACs) regulate diverse cellular processes, and are promising targets for a number of diseases. Here we describe the design and utilization of a largazole-based chemical probe to quantitatively measure the intracellular occupancy of HDAC1 and HDAC2 by dacinostat. Surprisingly, the probe was unable to enrich HDAC3 despite its nanomolar potency in a biochemical assay, further proving the necessity of cell-based target occupancy assays to understand compound potency in physiologically-relevant settings. This occupancy assay has the potential to aid the development of novel HDAC1/2 inhibitors in drug discovery.
摘要
组蛋白去乙酰化酶（HDACs）调节多种细胞过程，是多种疾病的潜在治疗靶点。在此，我们描述了一种基于拉戈唑的化学探针的设计与应用，用于定量测定西达本胺在细胞内对HDAC1和HDAC2的占有率。令人惊讶的是，尽管该探针在生化分析中具有纳摩尔级的活性，但它无法富集HDAC3，这进一步证明了基于细胞的靶点占有率分析对于理解化合物在生理相关环境中的活性的必要性。这种占有率分析有潜力在药物研发中助力新型HDAC1/2抑制剂的开发。
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