期刊
SLAS DISCOVERY
卷 22, 期 9, 页码 1093-1105出版社
SAGE PUBLICATIONS INC
DOI: 10.1177/2472555217717200
关键词
cancer and cancer drugs; enzyme assays or enzyme kinetics; natural products screening; tyrosyl-DNA phosphodiesterase
资金
- National Cancer Institute
- National Institutes of Health (NIH) [HHSN26120080001E]
- Intramural Research Program of the NIH
- Center for Cancer Research [BC006150]
Tyrosyl-DNA phosphodiesterase 1 (TDP1) is an enzyme crucial for cleavage of the covalent topoisomerase 1-DNA complex, an intermediate in DNA repair. TDP1 plays a role in reversing inhibition of topoisomerase I by camptothecins, a series of potent and effective inhibitors used in the treatment of colorectal, ovarian, and small-cell lung cancers. It is hypothesized that inhibition of TDP1 activity may enhance camptothecin sensitivity in tumors. Here, we describe the design, development, and execution of a novel assay to identify inhibitors of TDP1 present in natural product extracts. The assay was designed to address issues with fluorescent nuisance molecules and to minimize the detection of false-positives caused by polyphenolic molecules known to nonspecifically inhibit enzyme activity. A total of 227,905 purified molecules, prefractionated extracts, and crude natural product extracts were screened. This yielded 534 initial positives (0.23%). Secondary prioritization reduced this number to 117 (0.05% final hit rate). Several novel inhibitors have been identified showing micromolar affinity for human TDP1, including halenaquinol sulfate, a pentacyclic hydroquinone from the sponge Xestospongia sp.
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