Multi-Target, Mechanism-Based Drug Design for the Treatment of Breast Cancer: Syn

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DESCRIPTION (provided by applicant): Many studies have shown a correlation between the sphingolipid metabolism pathway and cancer pathogenesis as well as drug-resistance. The central molecule in sphingolipid metabolism, ceramide, is known to be involved in the induction of apoptosis, senescence and growth arrest in many human cancers, especially in breast cancer. However, its metabolites, sphingosine-1-phosphate and glucosylceramide lead to cellular transformation, proliferation and drug-resistance. Thus, elevation of ceramide levels and inhibition of ceramide metabolism are considered to be novel therapeutic targets for breast cancer treatment. Ceramide analogs can be designed to act as agonists of ceramide-activated effectors or inhibitors of ceramide-metabolizing enzymes. Also since this is a multi-target system, ceramide analogs naturally possess multiple possible mechanisms of actions. Therefore, we hypothesize that the use of diversity- oriented synthesis and screening, multi-target mechanism investigation, and systematic structure-activity relationship studies around ceramide analogs can generate multi-action agents for the treatment of breast cancer. To achieve the overall goal of this project, we propose three specific aims: 1. To synthesize novel ceramide analogs for screening as anti-cancer agents in breast cancer cell lines; 2. To determine the mechanisms of actions of the ceramide analogs found to be effective; and 3. To perform mechanism-based structure-activity relationship studies of ceramide analogs in breast cancer and build a pharmacophore model. We plan to synthesize three series of ceramide analogs in which modifications are made on the ceramide backbone and/or 1-hydroxy functional group. All of the newly synthesized ceramide analogs will be screened for viability inhibition and resistance-reversal in sensitive- and resistant- breast cancer cell lines. The inhibitors of cell viability will be further tested for pro-apoptotic activity as well as ceramidase and sphingosine kinase inhibition activities. Compounds causing resistance-reversal will be further studied in glucosylceramide synthase activity assays. Analogs with apoptotic activity will be studied to determine whether pro-apoptosis occurs via the mitochondrial pathway as in the case of ceramide. Through the above investigations, the mechanisms of actions of ceramide analogs will be identified and a large amount of activity data will be generated. Quantitative structure-activity relationship (QSAR) analysis will be carried out for each mechanism of action using computational chemistry. Furthermore a systematic pharmacophore model for ceramide-related molecules will be established. PUBLIC HEALTH RELEVANCE: Breast cancer is the second leading cause of death from cancer in American women, and resistance to current chemotherapeutics is the major cause of treatment failure. The purpose of this project is to develop a group of novel chemotherapeutic agents, which possess the capability of reversing drug-resistance. These dual-action chemotherapeutics designed based on the structure of ceramide, have the potential to play an important role in the treatment of breast cancer.