High-throughput identification of inhibitors of human mitochondrial peptide deformylase
High-throughput identification of inhibitors of human mitochondrial peptide deformylase
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DOI：
10.1177/1087057107300463
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发表时间：
2007-06-01
影响因子：
--
通讯作者：
Djaballah, Hakim
中科院分区：
文献类型：
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作者：
Antczak, Christophe;Shum, David;Djaballah, Hakim
人线粒体肽去甲酰基酶（HsPDF）为广泛作用的抗增殖药物提供了一个潜在的新靶点。为了鉴定新的非肽磁性和非羟酸基HsPDF抑制剂，作者开发了一种高通量筛选（HTS）策略，使用基于荧光极化（FP）的结合试验作为筛选化学文库的主要试验，然后使用基于酶的试验来确定其对已建立的肿瘤细胞系的抗增殖活性。作者介绍了在2880个化合物的中试筛选中所建立的策略的结果和性能，并确定了第一个抑制剂。在撞击中发现了两种常见的支架。此外，细胞毒性研究表明，大多数确认的命中具有抗增殖活性。这些发现表明，设计的策略可以识别新的功能抑制剂，并为HTS中使用功能测定提供了强有力的替代方案，并支持HsPDF抑制剂可能构成一类新的抗增殖剂的假设。
The human mitochondrial peptide deformylase (HsPDF) provides a potential new target for broadly acting antiproliferative agents. To identify novel nonpeptidomirnetic and nonhydroxamic acid-based inhibitors of HsPDF, the authors have developed a high-throughput screening (HTS) strategy using a fluorescence polarization (FP)-based binding assay as the primary assay for screening chemical libraries, followed by an enzymatic-based assay to confirm hits, prior to characterization of their anti proliferative activity against established turnor cell lines. The authors present the results and performance of the established strategy tested in a pilot screen of 2880 compounds and the identification of the 1st inhibitors. Two common scaffolds were identified within the hits. Furthermore, cytotoxicity studies revealed that most of the confirmed hits have antiproliferative activity. These findings demonstrate that the designed strategy can identify novel functional inhibitors and provide a powerful alternative to the use of functional assays in HTS and support the hypothesis that HsPDF inhibitors may constitute a new class of anti proliferative agent.