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Inhibitors of eIF4E/eIF4G Interaction as Potential Anti-Breast Cancer Drugs
Breast cancer is the most frequently occurring malignant disease in women. Translation of mRNA into protein is a tightly regulated process consisting of complicated multi-component systems responsible for initiation, elongation and termination. Translation initiation (TI) plays a critical role in the normal cellular homeostasis and in malignant transformation. On one hand, inhibition of TI preferentially reduces the synthesis of proteins such as growth factors and oncogenes. On the other hand, it increases the expression of a subset of mRNAs including the one encoding for the transcription factor ATF-4, which in turn upregulates the expression of the isoform of BRCA1, a critical tumor suppressor that is down-regulated in many breast and ovarian cancers. Development of effective inhibitors of TI may modulate synthesis of proteins essential for the expression of the malignant phenotype in breast cancer and suppress their tumorigenicity. Specifically, inhibition of the TI complex eIF4F (consist of eIF4E, eIF4G and eIF4A, the cap binding, scaffolding and helicase initiation factors, respectively) that is essential for the malignant transformation of human mammary epithelial cells and the maintenance of malignant phenotype. In this study we will develop potent inhibitors of the critical protein-protein interaction between eIF4E (4E) and eIF4G (4G). We hypothesize that employing eIF4E, the target protein, as a template to select building blocks with complementary reactive functionalities at a proximity that will allow in situ covalent bond formation will result in highly potent and specific inhibitors of 4E/4G interaction. We will 1) use our first generation inhibitors of 4E/4G interaction to construct libraries of building blocks; 2) use a small training set of building blocks to chemically synthesize a combinatorial library of ligands and test them for inhibition of 4E/4G interaction; And 3) use 4E as a template to select complementing building blocks and bring them to reacting proximity that will enable spontaneous "click" reaction. The formed products will be prepared chemically and submitted to full in vitro biological evaluation as inhibitors of 4E/4G interaction and translation initiation. If successful, this target-templated assembly of inhibitors will augment the classical and intuitive structure-activity relationship approach with a novel, powerful and intimate target directed approach for the development of effective TI inhibitors as mechanism-based anti-breast cancer drugs.
Breast cancer is the most frequently occurring malignant disease in women. It is caused by the spontaneous activation of cancer promoting genes, deletion and/or inactivation of tumor suppressing genes leading to cancer characterized by uncontrolled proliferation and survival. In a search for novel mechanism-based drugs to fight breast cancer, molecular processes essential for the development and maintenance of the malignant phenotype in the mammary tissue are targeted. Synthesis of proteins, the major building elements and machines of the living cell and organism is accomplished by tightly controlling the translation of mRNA transcribed from the DNA, the genetic blue-print. As such, the molecular machinery controlling initiation of mRNA translation is a complicated multi-component system including numerous checks and balances. Inhibition of translation initiation in cancer cells and lab animals reverses the malignant phenotype and inhibit tumor growth, respectively. It does it on one hand by preferential reduction of the synthesis of oncogenes, the cancer-promoting proteins required for cancer cell proliferation and survival, and on the other hand by increasing expression of a group of genes one of which is BRCA1, a critical tumor suppressor that is deficient in many breast and ovarian cancers. Effective inhibitors of translation initiation will modulate synthesis of proteins essential for the expression of the malignant phenotype in breast cancer and suppress their tumorigenicity. Specifically, disruption of the interaction between translation initiation factors: eIF4E, the cap binding protein, and eIF4G, the scaffolding protein, will block the formation of the eIF4F complex, which is essential for the transformation of human mammary epithelial cells and their survival and proliferation. In this study we will employ a novel and a powerful approach to develop small molecules that bind to eIF4E and prevent it from interacting with eIF4G. Chemical libraries of building blocks, derived from first generation inhibitors of eIF4E/eIF4G interaction, discovered in our lab, will be synthesized. The target protein eIF4E will serve as a template to select complementing building blocks and bring them together to enable spontaneous assembly of novel and highly potent inhibitors of eIF4E/eIF4G interaction. If successful, this target-based assembly of building blocks will lead to potent inhibitors of translation initiation and effective anti-breast cancer drugs.