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Development and Use of a High-Throughput Bacterial DNA Gyrase Assay to Identify Mammalian Topoisomerase II Inhibitors with Whole-Cell Anticancer Activity

Kendel International Inc., 1200 Karew Tower, 441 Vine St., Cincinnati, OH 45202. sid@kendle.com

Kelly M. Makin

Tracy L. Twinem

David T. Stanton

Sandra L. Nelson

Carl E. Catrenich

A high-throughput screen (HTS)was developed and used to identify inhibitors of bacterial DNA gyrase. Among the validated hits were 53 compounds that also inhibited mammalian topoisomerase II with IC₅₀ values of <12.5 µg/mL for 51 of them. Using computational methods, these compounds were subjected to cluster analysis to categorize them according to their chemical and structural properties. Nine compounds from different clusters were tested for their whole-cell inhibitory activity against 3 cancer cell lines—NCI-H460 (lung), MCF7 (breast), and SF-268 (CNS)—at a concentration of 100 µM. Five compounds inhibited cell growth by >50% for all 3 cell lines tested. These compounds were tested further against a panel of 53 to 57 cell lines representing leukemia, melanoma, colon, CNS, ovarian, renal, prostate, breast, and non–small cell lung cancers. In this assay, PGE-7143417 was found to be the most potent compound, which inhibited the growth of all the cell lines by 50% at a concentration range of 0.31 to 2.58 µM, with an average of 1.21 µM. An additional 17 compounds were also tested separately against a panel of 10 cell lines representing melanoma, colon, lung, mammary, ovarian, prostate, and renal cancers. In this assay, 4 compounds—PGE-3782569, PGE-7411516, PGE-2908955, and PGE-3521917—were found to have activity with concentrations for 50% cell growth inhibition in the 0.59 to 3.33, 22.5 to 59.1, 7.1 to >100, and 24.7 to >100 µM range. (Journal of Biomolecular Screening 2003:157-163)

Key Words: high-throughput screening • bacterial DNA gyrase • topoisomerase II • anticancer agents

Journal of Biomolecular Screening, Vol. 8, No. 2, 157-163 (2003)
DOI: 10.1177/1087057103252302


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