The type II topoisomerases – enzymes that manage tangles and supercoils in DNA – exist in all organisms and are important drug targets. Widely prescribed anticancer agents including etoposide and doxorubicin target human type II topoisomerases, and quinolone antibiotics such as ciprofloxacin target bacterial topoisomerases.
Clinically relevant quinolones have no activity against human type II topoisomerases, but a series of experimental quinolones have high activity against both bacterial and human topoisomerases. To understand the basis for this quinolone cross-reactivity, Neil Osheroff, Ph.D., and colleagues analyzed the activity of one of the experimental compounds (CP-115,955) and a series of related quinolones and quinazolinediones against type II topoisomerases from Bacillus anthracis and humans.
They found that CP-115,955 uses different structural features, which they defined, to recognize both bacterial and human enzymes. The findings, reported in the Feb. 10 issue of Biochemistry, suggest that the CP-115,955 series quinolones may be a good starting point for developing novel topoisomerase II-targeted drugs with anticancer potential.
This work was supported by grants from the National Institutes of Health (AI081775, AI087671, GM033944) and by a United States Veterans Administration Merit Review Award.
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