High Throughput Discovery, Metabolism and Disposition of Chemopreventive Agents using Mass Spectrometry
thesisposted on 2013-06-28, 00:00 authored by Lian Chen
Cancer chemoprevention uses natural, synthetic, or biologic chemical agents to reverse, suppress or prevent the initial, promotion and/or progression of cancer. The successful development of new chemotherapeutic agents that target specific signal transduction pathways and achieve dramatic improvements in efficacy without significant cytotoxicity will be important for the future of cancer chemoprevention. As a nuclear receptor, the retinoid X receptor (RXR) is involved in the regulation of multiple anti-cancer pathways including several of those involved in cell proliferation, differentiation and apoptosis. Ligand-mediated activation of the RXR is a strategy for cancer chemoprevention and therapy. Ultrafiltration mass spectrometric screening greatly facilitated the screening for ligands of RXRα. AM6-36 was identified as structurally unique rexinoid and a leading chemopreventive agent based in high throughput screening. The preliminary metabolism studies of AM6-36 suggest that AM6-36 will not form reactive, potentially toxic metabolites. AM6-36 showed moderate serum protein binding, moderate metabolic stability, and low first-pass liver metabolism is predicted. These properties are favorable for further investigation and development of AM6-36 as a potential chemoprevention and cancer therapeutic agent. Two Topoisomerase I inhibotors, indimitecan (LMP776) and indotecan (LMP400) were promoted into Phase I clinical trials at the National Cancer Institute. These compounds appear to be stable and are powerful, cytotoxic Top1 poisons that induce long-lasting DNA breaks and overcome the drug resistance issues associated with the camptothecins. The metabolism of LMP400 and LMP776 is currently under investigation, which has led to the synthesis of potential metabolites to be used as synthetic standards for metabolism studies. O-dealkylation and demethylenation are two major metabolic pathways of LMP400 and LMP776 observed to occur in human liver microsomes. In conclusion, LC-MS has provided superior sensitivity and selectivity needed for analytical challenges, making it well suited for drug metabolism as well as other ADME related evaluation of lead compounds from screening.
Advisorvan Breemen, Richard B.
DepartmentMedicinal Chemistry and Pharmacognosy
Degree GrantorUniversity of Illinois at Chicago
Committee MemberBurdette, Joanna E. Franzblau, Scott G. Murphy, Brian T. Jeong, Hyun-Young