The primary aim of Project 2 was to use unbiased high throughput screening (HTS) of small molecule libraries allied to more targeted approaches to identify novel compounds that would protect and mitigate against radiation damage, primarily to the immunohematopoietic system but also other tissues. The theory was that active compounds would possess a molecular and/or chemical signature that could be identified and optimized to benefit the development of superior agents for Stockpiling in case of a radiologic disaster. We have shown that tetracyclines, quinolones, and cyclopiazonic acid can act as radiation mitigators, independent of any anti-microbial action. Furthermore, they share a common metal-binding pharmacophore. The importance of this substructure for mitigation will be studied in the next funding period. Other active mitigators included purine nucleosides. We intend to explore this avenue further using new compounds that are specific for differentially expressed subtypes of adenosine receptors so as to minimize possible mutually antagonistic actions and side effects resulting from the use of these agents. Linoleate and other polyunsaturated fatty acids also showed mitigating activity, as did several other agents that are directed to Toll-like receptors or are products of these pathways. This link will be investigated furter in collaboration with Project 3. Compounds from the chemically defined libraries that were positive in our screens will be investigated further along with Project 1, which showed that two ofthe compounds were positive in yeast DEL HTS assays and in vivo as mitigators. Our working hypothesis is that radiation initiates continuing "waves" of integrated molecular and cellular responses that are aimed at tissue regeneration and that multiple mitigators may be needed, perhaps given at different times, to rebalance tissue homeostasis. This will require mechanistic knowledge of how these mitigators work. We have shown effects ranging from DNA repair to stimulating hematopoiesis to long-term animal survival. In vitro assays will be extended to include novel epithelial and stem cell assays developed through the Pilot Project mechanism and in vivo assays will be extended to include better coverage of effects of sublethal damage and stem cell recovery.
There is a dearth of agents available for the treatment and management of patients exposed to radiation. This project has discovered novel agents and aims to optimize them further to improve their effectiveness. Our search for agents that mitigate radiation damage is linked to identifying their molecular and/or chemical signatures and the mechanism by which they work, which in turn might tell us how best to adminster them.
|Micewicz, Ewa D; Sharma, Shantanu; Waring, Alan J et al. (2016) Bridged Analogues for p53-Dependent Cancer Therapy Obtained by S-Alkylation. Int J Pept Res Ther 22:67-81|
|Wang, Wenyuan; Org, Tonis; Montel-Hagen, AmÃ©lie et al. (2016) MEF2C protects bone marrow B-lymphoid progenitors during stress haematopoiesis. Nat Commun 7:12376|
|Ratikan, Josephine A; Micewicz, Ewa D; Xie, Michael W et al. (2015) Radiation takes its Toll. Cancer Lett 368:238-45|
|Micewicz, Ewa D; Ratikan, Josephine A; Waring, Alan J et al. (2015) Lipid-conjugated Smac analogues. Bioorg Med Chem Lett 25:4419-27|
|Micewicz, Ewa D; Bahattab, Omar S O; Willars, Gary B et al. (2015) Small lipidated anti-obesity compounds derived from neuromedin U. Eur J Med Chem 101:616-26|
|Pai, Melody Y; Lomenick, Brett; Hwang, Heejun et al. (2015) Drug affinity responsive target stability (DARTS) for small-molecule target identification. Methods Mol Biol 1263:287-98|
|Schaue, DÃ¶rthe; Micewicz, Ewa D; Ratikan, Josephine A et al. (2015) Radiation and inflammation. Semin Radiat Oncol 25:4-10|
|Schaue, DÃ¶rthe; McBride, William H (2015) Opportunities and challenges of radiotherapy for treating cancer. Nat Rev Clin Oncol 12:527-40|
|Damoiseaux, Robert (2014) UCLA's Molecular Screening Shared Resource: enhancing small molecule discovery with functional genomics and new technology. Comb Chem High Throughput Screen 17:356-68|
|Erde, Jonathan; Loo, Rachel R Ogorzalek; Loo, Joseph A (2014) Enhanced FASP (eFASP) to increase proteome coverage and sample recovery for quantitative proteomic experiments. J Proteome Res 13:1885-95|
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