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.
|Gu, Lubing; Zhang, Hailong; Liu, Tao et al. (2018) Inhibition of MDM2 by a Rhein-Derived Compound AQ-101 Suppresses Cancer Development in SCID Mice. Mol Cancer Ther 17:497-507|
|Pan, Zhixiang; Chittavong, Vayou; Li, Wei et al. (2017) Organic CO Prodrugs: Structure-CO-Release Rate Relationship Studies. Chemistry 23:9838-9845|
|Wang, Wenyi; Ji, Xingyue; Du, Zhenming et al. (2017) Sulfur dioxide prodrugs: triggered release of SO2via a click reaction. Chem Commun (Camb) 53:1370-1373|
|Liu, T; Xiong, J; Yi, S et al. (2017) FKBP12 enhances sensitivity to chemotherapy-induced cancer cell apoptosis by inhibiting MDM2. Oncogene 36:1678-1686|
|Ji, Xingyue; Ji, Kaili; Chittavong, Vayou et al. (2017) Click and Fluoresce: A Bioorthogonally Activated Smart Probe for Wash-Free Fluorescent Labeling of Biomolecules. J Org Chem 82:1471-1476|
|Zheng, Yueqin; Yu, Bingchen; Ji, Kaili et al. (2016) Esterase-Sensitive Prodrugs with Tunable Release Rates and Direct Generation of Hydrogen Sulfide. Angew Chem Int Ed Engl 55:4514-8|
|Ji, Xingyue; Damera, Krishna; Zheng, Yueqin et al. (2016) Toward Carbon Monoxide-Based Therapeutics: Critical Drug Delivery and Developability Issues. J Pharm Sci 105:406-416|
|Gu, Lubing; Zhang, Hailong; Liu, Tao et al. (2016) Discovery of Dual Inhibitors of MDM2 and XIAP for Cancer Treatment. Cancer Cell 30:623-636|
|Liu, Tao; Zhang, Hailong; Xiong, Jing et al. (2015) Inhibition of MDM2 homodimerization by XIAP IRES stabilizes MDM2, influencing cancer cell survival. Mol Cancer 14:65|
|Zhang, Hailong; Liu, Tao; Yi, Sha et al. (2015) Targeting MYCN IRES in MYCN-amplified neuroblastoma with miR-375 inhibits tumor growth and sensitizes tumor cells to radiation. Mol Oncol 9:1301-11|
Showing the most recent 10 out of 11 publications