High-throughput identification of inhibitors of human mitochondrial peptide deformylase Journal Article
| Authors: | Antczak, C.; Shum, D.; Escobar, S.; Bassit, B.; Kim, E.; Seshan, V. E.; Wu, N.; Yang, G.; Ouerfelli, O.; Li, Y. M.; Scheinberg, D. A.; Djaballah, H. |
| Article Title: | High-throughput identification of inhibitors of human mitochondrial peptide deformylase |
| Abstract: | The human mitochondrial peptide deformylase (HsPDF) provides a potential new target for broadly acting antiproliferative agents. To identify novel nonpeptidomimetic 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 antiproliferative activity against established tumor 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 antiproliferative agent. © 2007 Society for Biomolecular Sciences. |
| Keywords: | controlled study; unclassified drug; human cell; drug activity; enzyme inhibition; embryo; cell line; antineoplastic activity; cytotoxicity; high throughput screening; fluorescence polarization; drug mechanism; enzyme inhibitors; tumor cell line; hematoxylin; epigallocatechin gallate; peptide deformylase; actinonin; amidohydrolases; mitochondria; mitochondrion; enzyme assay; jurkat cells; high-throughput screening; k562 cells; peptide deformylase inhibitor; binding assay; antiproliferative agents; human peptide deformylase; spectrometry, mass, electrospray ionization; hl-60 cells; 2',2' bisepigallocatechin monogallate; 3 methoxycatechol; 7,8 dihydroxyflavone; chloranil; epitheaflavin monogallate; gallic acid derivative; hematin; human mitochondrial peptide deformylase; irigenol; purpurin derivative; purpurogallin; pyrogallol; quinalizarin; theaflavin; thiram; fluorescence polarization immunoassay |
| Journal Title: | Journal of Biomolecular Screening |
| Volume: | 12 |
| Issue: | 4 |
| ISSN: | 1087-0571 |
| Publisher: | Sage Publications |
| Date Published: | 2007-06-01 |
| Start Page: | 521 |
| End Page: | 535 |
| Language: | English |
| DOI: | 10.1177/1087057107300463 |
| PUBMED: | 17435169 |
| PROVIDER: | scopus |
| PMCID: | PMC2234356 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 15" - "Export Date: 17 November 2011" - "CODEN: JBISF" - "Source: Scopus" |
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