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High-Throughput Identification of Inhibitors of Human Mitochondrial Peptide DeformylaseHigh Throughput Screening Core Facility, Memorial Sloan-Kettering Cancer Center, New York, New York
High Throughput Screening Core Facility, Memorial Sloan-Kettering Cancer Center, New York, New York
Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Center Center, New York, New York
Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Center Center, New York, New York
High Throughput Screening Core Facility, Memorial Sloan-Kettering Cancer Center, New York, New York
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Center Center, New York, New York
Analytical Pharmacology Core Facility, Memorial Sloan-Kettering Center Center, New York, New York
Organic Synthesis Core Facility, Memorial Sloan-Kettering Cancer Center, New York, New York
Organic Synthesis Core Facility, Memorial Sloan-Kettering Cancer Center, New York, New York
Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Center Center, New York, New York
Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Center Center, New York, New York
High Throughput Screening Core Facility, Memorial Sloan-Kettering Cancer Center, New York, New York, djaballh{at}mskcc.org 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. (Journal of Biomolecular Screening 2007:521-535)
Key Words: human peptide deformylase • high-throughput screening • fluorescence polarization • antiproliferative agents
This version was published on June
1, 2007 Journal of Biomolecular Screening, Vol. 12, No. 4,
521-535 (2007) This article has been cited by other articles:
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