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- Title
High throughput screening of small molecule libraries for modifiers of radiation responses.
- Authors
Kim, Kwanghee; Damoiseaux, Robert; Norris, Andrew J; Rivina, Leena; Bradley, Kenneth; Jung, Michael E; Gatti, Richard A; Schiestl, Robert H; McBride, William H
- Abstract
An unbiased approach of drug discovery through high-throughput screening (HTS) of libraries of chemically defined and bioactive small molecule compounds was used to identify modulators of radiation injury with an emphasis on radioprotectors and mitigators rather than radiosensitisers. Assay system endpoints included radiation-induced genotoxicity and DNA damage in yeast and apoptosis in murine lymphocytes. Large-scale data mining of chemically diverse libraries identified agents that were effective with all endpoints. HTS of bioactive compound libraries against murine lymphocytes profiled tetracycline and fluoroquinolone antibiotics and cyclopiazonic acid as having activity, and structure-activity analysis showed a common pharmacophore. Purine nucleosides, the interferon inducer tilorone, and linoleic acid were also identified as potential mitigators of radiation damage that often were also radioprotective. Many of these compounds enhance DNA repair, have anti-inflammatory activity, and stimulate hematopoiesis. Selected compounds within these initial verified hits from both types of libraries identified potent mitigators of lethal whole body irradiation (WBI) in mice.
- Publication
International journal of radiation biology, 2011, Vol 87, Issue 8, p839
- ISSN
1362-3095
- Publication type
Journal Article
- DOI
10.3109/09553002.2011.560994