The Effect of Potential PDK1 Inhibitors on Metastatic Cancers in African American

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The long-term goal of the Pi's research program is to evaluate the structural specification of the benzimidazole molecules relating to the ability of the molecules to inhibit PDK1 activity and PDK1 mediate cell proliferation. The disparity of prostate cancer among African Americans has been attributed to a number of social and biological factors. It has been noted that a diet rich in cholesterol is linked to the over expression of cavoelin-1 in African Americans diagnosed with prostate cancer. Cavelin-1 enhances the activity of phosphoinositide dependent kinase 1 (PDK1), a critical component of the Phosphatidylinositol 3- kinase/Protein Kinase B (PISK/Akt) signaling pathway. The overexpression of components of this pathway contributes to the progression and development of many tumors. As a result, PDK1 has been at the center of drug design strategies for prostate cancer therapies. However, a comparative analysis of the effects of such agents in African Americans and Caucasians has not been reported. Therefore, this research seeks to evaluate the proposed library of compounds to determine affects on the regulation of PDK1. Potentially, binding interactions of the molecules and PDK1 can be analyzed and the hypothesis can be tested that benzimidazole-based molecules will effectively inhibit PDK1 and prevent PDK1- dependent proliferation of prostate cancer cells in late stage African-American and Caucasian models. The following specific aim will be carried out to test this hypothesis: (1) To synthesize a set of benzimidazole molecules. (2) To analyze the biological activity of the molecules. The synthesized molecules will be evaluated for their ability to inhibit cell proliferation, ATP binding in PDK1 and PDK1 dependent phosphorylation. (3) To determine the Absorption, Distribution, Metabolism, Elimination and Toxicity (ADMETox) and Quantitative Structure-Activity Relationship (QSAR). Successful completion of the project should show that the molecules are able to prevent ATP binding to PDK1 and the subsequent phosphorylation of Akt. Such activity should show the potential of the molecule to circumvent the elevated levels of caveolin-1 in African-American which leads to increased PDK1 activity. The work will be useful in the design of molecule effective against prostate cancer n African-Americans.