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A Profiling Platform for the Identification of Selective Metalloprotease Inhibitors

High Throughput Screening Core Facility Molecular Pharmacology and Chemistry Program Memorial Sloan-Kettering Cancer Center 1275 York Avenue, New York,

Constantin Radu

High Throughput Screening Core Facility Molecular Pharmacology and Chemistry Program Memorial Sloan-Kettering Cancer Center 1275 York Avenue, New York,

Hakim Djaballah

High Throughput Screening Core Facility Molecular Pharmacology and Chemistry Program Memorial Sloan-Kettering Cancer Center 1275 York Avenue, New York, NY 10065, djaballh{at}mskcc.org

Although proteases represent an estimated 5% to 10% of potential drug targets, inhibitors for metalloproteases (MPs) account for only a small proportion of all approved drugs, failures of which have typically been associated with lack of selectivity. In this study, the authors describe a novel and universal binding assay based on an actinonin derivative and show its binding activities for several MPs and its lack of activity toward all the non-MPs tested. This newly developed assay would allow for the rapid screening for inhibitors of a given MP and for the selectivity profiling of the resulting hits. The assay has successfully enabled for the first time simultaneous profiling of 8 well-known inhibitors against a panel of selected MPs. Previously published activities for these inhibitors were confirmed, and the authors have also discovered new molecular targets for some of them. The authors conclude that their profiling platform provides a generic assay solution for the identification of novel metalloprotease inhibitors as well as their selectivity profiling using a simple and homogeneous assay. (Journal of Biomolecular Screening 2008:285-294)

Key Words: metalloprotease • inhibitor • profiling • fluorescence polarization • HTS

This version was published on April 1, 2008

Journal of Biomolecular Screening, Vol. 13, No. 4, 285-294 (2008)
DOI: 10.1177/1087057108315877


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