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

PI研究计划的长期目标是评估PIC的结构规范 苯并咪唑类分子抑制PDK1活性及PDK1介导性的研究 细胞增殖。在非裔美国人中前列腺癌的差异被归因于许多 社会和生物因素的影响。人们已经注意到，富含胆固醇的饮食与肥胖有关。 非裔美国人前列腺癌组织中Caveelin-1的表达。Cavelin-1增强了 磷脂酰肌醇3的关键成分--磷脂酰肌醇依赖激酶1的活性 Pisk/Akt信号通路。这一途径各组成部分的过度表达 有助于许多肿瘤的进展和发展。因此，PDK1一直处于中心地位 前列腺癌治疗的药物设计策略。然而，通过比较分析，可以看出， 非洲裔美国人和高加索人中的这种药物还没有报道。因此，这项研究试图 评估建议的化合物文库，以确定对PDK1调节的影响。有可能， 可以分析分子与PDK1的结合作用，并且可以检验假设 苯并咪唑类分子将有效抑制PDK1，防止PDK1依赖的细胞增殖 晚期非裔美国人和高加索人模型中的前列腺癌细胞。以下具体目标将 来验证这一假设：(1)合成一组苯并咪唑分子。(2)分析 分子的生物活性。合成的分子将被评估它们抑制的能力 细胞增殖、PDK1中的ATP结合和PDK1依赖的磷酸化。(三)确定 ADMETox的吸收、分布、代谢、消除和毒性与定量构效关系 关系(QSAR)。该项目的成功完成应该表明这些分子能够 阻止ATP与PDK1结合以及随后Akt的磷酸化。这样的活动应该显示出 该分子可能绕过非裔美国人体内升高的小窝蛋白-1水平，从而导致 PDK1活性增加。这项工作将为设计有效的抗前列腺癌分子提供参考。 N个非洲裔美国人。

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.