The location of translation initiation at the apex of many well-defined oncogenic, pro-apoptotic and tumor-suppressor pathways makes it an attractive target for the development of anti-cancer agents and represents a new paradigm in cancer therapy. Because restoration of translational control down-regulates oncogenic proteins with minimal effect on housekeeping proteins, small molecule inhibitors of translation initiation have excellent potential for achieving a wide therapeutic window. The emergence of translation initiation inhibitors as a new class of anticancer drugs is consistent with the current view that modern anti-cancer therapy must be target-specific and inhibit the growth of cancer cells but not of normal cells, a distinct difference from still-prevalent genotoxic therapies. The goal of this proposal is to execute a hit-to-lead optimization of #4EGI-1, a thiazolyl-hydrazone propionic acid (THPA) derivative to obtain a potent and selective preclinical lead candidate. The #4EGI-1, identified in our laboratories by high throughput screening of chemical libraries inhibits eIF4E/eIF4G interaction that is essential for the formation of eIF4F complex (a critical regulatory step in the translation initiation cascade) is an inhibitor of cap-dependent translation. The structure-based optimization will combine insights gained from the NMR- and docking studies that resulted in a model of eIF4E-#4EGI-1 complex, preliminary medicinal chemistry that identified the putative pharmacophore and performed a limited structure-activity relationship studies, a panel of in vitro assays that include: 1. competitive binding to eIF4E, 2. inhibition of cancer cell growth, 3. pull-down experiment to demonstrate disruption of eIF4F complex, and 4. inhibition of cap dependent translation in cell extracts, and a xenograft mouse model of human cancer. Our integrative and iterative strategy will include two tier elaboration of the THPA scaffold. Initially, we will design focused libraries directed toward the substituent at position 3 of the propionic acid, and positions 4 and 5 of the thiazolidine ring aiming to enhance interaction with the hot spot and putative exosites on eIF4E. In addition, we will rigidify the THPA scaffold to lock it in either E or Z configuration around the exocyclic C=N in order to prevent spontaneous isomerization thus characterizing the bioactive configuration. Taken together, our effort will lead to the development of a potent and selective preclinical anti-cancer drug candidate targeting the eIF4F complex. PUBLIC HEALTH REVELANCE: The location of translation initiation at the apex of many well-defined oncogenic, pro-apoptotic and tumor- suppressor pathways makes it an attractive target for the development of anti-cancer agents and represents a new paradigm in cancer therapy. Because restoration of translational control down-regulates oncogenic proteins with minimal effect on housekeeping proteins, small molecule inhibitors of translation initiation have excellent potential for achieving a wide therapeutic window. We plan to carry out a hit-to-lead optimization of #4EGI-1 a small molecule inhibitor of eIF4E/eIF4G interaction, which is a crucial player in the translation initiation cascade, in an effort to identify a potent and selective preclinical candidate. ? ? ?
