The use of diversity profiling to characterize chemical modulators of the histone deacetylases
The use of diversity profiling to characterize chemical modulators of the histone deacetylases
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DOI：
10.1016/j.lfs.2008.03.004
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发表时间：
2008-05-23
期刊：
影响因子：
6.1
通讯作者：
Janzen, William P.
中科院分区：
文献类型：
--
作者：
Blackwell, Leonard;Norris, Jacqueline;Janzen, William P.
在大多数激酶项目的药物发现的早期阶段，对靶特异性和脱靶倾向进行常规监测。通常，这些标准使用由体外激酶测定的不同集合组成的分析小组进行评估，并将化合物结构与效力和选择性相关联。这些努力的成功导致了磷酸酶、蛋白酶和表观遗传靶点的类似小组的设计。在这里，由11个组蛋白脱乙酰基酶（HDAC）和1个组蛋白乙酰转移酶（HAT）组成的表观遗传分析面板的实施被用于评估这些酶的化学调节剂。HDAC抑制剂（HDACi），如丁酸钠和阿司他丁A表现出不同的生物学效应，这导致了对它们在多种疾病状态中的治疗潜力的广泛猜测。一些HDAG已经在体内表现出肿瘤抑制作用，最近Zolinza是FDA批准用于治疗皮肤T细胞淋巴瘤的第一个HDAG。虽然HDACi已经证明了治疗效用，但许多第一代化合物是泛抑制剂。因此，使用HDAC谱板将是实现下一代抑制剂的亚型特异性所必需的。为此，测试了21种化合物，其中12种已知对HDAC具有活性，以评估表观遗传组的效用。此外，这些化合物针对由激酶、磷酸酶和蛋白酶活性组成的较大的72个成员酶组进行了测试。这一努力代表了这些化合物第一次被描述为具有如此广泛的生物化学活性。(c)2008年爱思唯尔公司All rights reserved.
Target specificity and off-target liabilities are routinely monitored during the early phases of drug discovery for most kinase projects. Typically these criteria are evaluated using a profiling panel comprised of a diverse collection of in vitro kinase assays and relates compound structure to potency and selectivity. The success of these efforts has led to the design of similar panels for phosphatase, protease, and epigenetic targets. Here the implementation of an epigenetic profiling panel, comprised of eleven histone deacetylases (HDACs) and one histone acetyltransferase (HAT), was used to evaluate chemical modulators of these enzymes. HDAC inhibitors (HDACi) such as sodium butyrate and trichostatin A demonstrate diverse biological effects which have led to broad speculation about their therapeutic potential in multiple disease states. Some HDAG have demonstrated tumor suppression in vivo and recently Zolinza was the first HDAG approved by the FDA for the treatment of cutaneous T-cell lymphoma. While HDACi have demonstrated therapeutic utility, many of the first generation compounds are pan-inhibitors. Thus, use of an HDAC profiling panel will be essential in achieving isoform specificity of the next generation of inhibitors. To this end, twenty-one compounds, twelve of which are known to have activities against the HDACs, were tested to evaluate the utility of the epigenetic panel. Additionally, these compounds were tested against a larger 72 member enzyme panel comprised of kinase, phosphatase and protease activities. This effort represents the first time these compounds have been profiled with such a broad range of biochemical activities. (c) 2008 Elsevier Inc. All rights reserved.