In this application, it is proposed to create an NCDDG for the development of small molecule inhibitors of translation initiation, a novel class of mechanism-specific anti-cancer drugs. Recent research shows that translation initiation factors contribute to initiation of cancer and may be required for its maintenance. This is because most oncogenes possess long, highly structured G/C-rich 5'UTRs and their synthesis, is, therefore, highly dependent on translational initiation factors such as eIF2 and Eif4. The proposed research is based on the recent discovery in the principal investigator's laboratory that down-regulation of translation initiation factors by a distinct series of compounds that deplete intracellular calcium stores, abrogates translational initiation and thereby synthesis of G1 cyclins,, and blocks the cell cycle in the G1 phase. These compounds, that include clotrimazone and a series of analogues synthesized in collaboration with PharmEco, a member of this NCDDG, exert potent anti-cancer activity in cells and in animal cancer models. The structure and the interactions of many translation initiation factors including eIF4E and eiF4G have been elucidated mainly by Dr. G. Wagner, a third member of this NCDDG. To develop inhibitors of translation for cancer therapy, the NCDDG will identify, in a structure-based search, lead compounds that inhibit translation initiation by blocking the interaction of eIF4E with 7MGpp cap or eIF4G, or that activated the PKR, the eIF2 inhibitory kinase, either directly or by depleting calcium stores. The proposed research takes advantage of recent advances in combinatorial chemistry, parallel synthesis and information technology that allows the rational design, synthesis and screening of thematic libraries of large numbers of compounds. Since the evaluation and further development of large numbers of compounds require mechanism-based assays amenable to automation, we propose to develop and validate target specific assays for inhibitors of translation initiation. Specifically we propose to develop cell based and in vitro binding and mechanism-specific functional assays to test for the different subclasses of inhibitors of translation initiation in a high throughput format. We will also develop mechanism specific animal cancer models to evaluate the efficacy and validate the mechanism of action of the anti-cancer drugs developed through the NCDDG effort. Eventually, we expect to optimize 1-2 subclasses of translation developed through this NCDDG effort. Eventually, we expect to optimize 1-2 subclasses of translation initiation inhibitors up to the point of their clinical evaluation for treatment and, perhaps, prevention of cancer.
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