In cancer treatment, the key is to focus on cancer-specific targets and thereby reduce side effects. Along this line, we are interested in exploring the possibility of using certain anthraquinone analogs to target MDM2 and/or MDM4 for the development of cancer treatment options. This revised application is based on extensive preliminary results examining certain anthraquinone analogs, which specifically inhibit the interactions between MDM2 and MDM4 and thus increase the level of p53, which in turn results in apoptosis of cancer cells. Initial animal studies with an acute lymphoblastic leukemia (ALL) mouse model indicated cure at the 1-year point (the duration of the experiments) after only two weeks of treatment, while all mice without treatment died within 45 days as expected. Preliminary studies also suggest that the identified compounds show minimal or no toxicity to normal cells, and in animal studies including pathological studies of heart, kidney, and liver, presumably due to the fact that levels of MDM2 and MDM4 are only elevated in cancer, not normal cells. In this application, we plan to understand and validate the mechanism(s) and examine the feasibility of inhibiting MDM2-MDM4 interaction as a way to develop cancer therapeutics. We plan to use acute lymphoblastic leukemia (ALL) as a model because of our extensive experience in this area.
Specific Aims i nclude (1) study the structure-activity relationship (SAR) of the anthraquinone analogs with regard to their ability to induce apoptosis;(2) define the molecular mechanism(s) of action of anthraquinone analogs;and (3) further ascertain the potential of developing anthraquinone analogs as viable candidates for ALL treatment using animal models. Upon completion of the proposed work, we hope to have (1) fully demonstrated the feasibility of targeting MDM2-MDM4 interactions as a way to develop new anticancer agents;(2) defined the molecular mechanism and structure-activity relationship for this class of anthraquinones, (3) fully established animal models for further preclinical evaluation, and (4) possibly identified viable candidates for preclinical GLP/GMP work in preparation for future clinical studies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA180519-01A1
Application #
8783378
Study Section
Special Emphasis Panel (ZRG1-BCMB-X (02))
Program Officer
Fu, Yali
Project Start
2014-09-12
Project End
2019-08-31
Budget Start
2014-09-12
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$460,311
Indirect Cost
$82,908
Name
Georgia State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
837322494
City
Atlanta
State
GA
Country
United States
Zip Code
30302
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