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N'N'Diarylurea Inhibitors of Translation Initiation for Treatment of Breast Cancer
Scientific Abstract Breast cancer is the second leading cause of cancer related deaths in the United States. It is characterized by increased expression of oncogenic proteins and reduced expression of tumor suppressor genes. Translation of mRNA into protein is tightly regulated at the level of initiation and plays a critical role in regulation of gene expression. Deregulation of translation initiation (TI) critically contributes to the development of malignant phenotypes. Conversely, inhibition of translation initiation abrogates cancer cell proliferation in vitro and reduce tumor growth in vivo. On a cellular level inhibition of TI preferentially reduces the synthesis of proteins such as growth factors and oncogenes while favoring translation of a subset of mRNAs including the ones encoding for the transcription factor ATF-4 and a poorly translated isoform of BRCA1, a critical tumor suppressor that is down-regulated in many breast and ovarian cancers. Taking advantage of this gene specific regulation by TI inhibitors we developed a cell based high throughput dual luciferase reporter assay and screened collection of 120,000 chemical compounds. This effort resulted in identification of N?N?-diarylureas as a privileged scaffold. Bioassay guided structure activity relationship (SAR) studies resulted in development compounds with ~ 200 nM activity in human breast cancer cell proliferation assays. In this study we propose to determine pharmacokinetic and acute toxicity profiles of lead compounds, optimize these agents if needed, and study their in vivo efficacy for treatment of breast cancer. Specifically we propose to 1) use our current lead compounds to determine their plasma half-life times, maximum tolerated dose, lethal dose 10, 50 and 90, if needed optimizing them for in vivo stability and safety by limited modifications, and 2) Determine their in vivo efficacy for treatment of breast cancer using animal models of human breast cancer. If successful, these inhibitors of translation initiation will offer a novel, mechanism specific alternative to chemo-toxic agents for treatment of breast cancer.
Lay Abstract Breast cancer is the most prevalent cancer in women, responsible for 400,000 cases and 40,000 deaths a year. Breast cancer characterized by abnormalities in the structure and function of genes required for maintenance of physiologic controls on cell proliferation and survival. Novel agents that destroy breast cancer cells with minimal effect on normal cells are urgently needed to fight breast cancer. These agents should target molecular processes essential for the development and maintenance of the breast cancer. Conversion of genetic code from DNA to building blocks of human body requires transcription of DNA into mRNA and translation of mRNA into proteins, which carry out all cellular processes. Translation of mRNA is tightly regulated at the level of initiation to ensure that proper balance of proteins is maintained in the cells. In breast cancer cells this balance is perturbed such that it favors uncontrolled growth. This applicant has demonstrated that inhibition of translation initiation by small molecular weight agents reverses malignant phenotype in cancer cells and in animal models of cancer. This is because restoration of translation initiation to normal levels reduces the production of the cancer-promoting proteins called oncogenes while increasing expression of a group of genes called tumor suppressors. This restored balance is deadly for cancer cells because they depend on uncontrolled expression of oncogenes and on inhibition of tumor suppressor genes for survival. We have developed a high throughput assay to identify agents that inhibit translation initiation. Utilizing this assay we identified agents that potently inhibit proliferation of breast cancer cell lines in vitro. One class of these agents was further optimized by chemical synthesis and in vitro testing. In this application we propose to extent these studies to animal models as a prelude to determining their utility for treatment of breast cancer. Specifically we will determine the pharmacokinetics of these compounds in animals, study their acute toxicity and design and synthesize their more stable and less toxic forms if needed. We will then test the optimal agents in tumor bearing animals for breast cancer therapy. If successful, this effort will lead to development of novel drugs for breast cancer treatment.