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

潜在 PDK1 抑制剂对非裔美国人转移性癌症的影响

• 批准号: 7434722
• 负责人: Leyte L Winfield
• 金额: $ 28万
• 依托单位: SPELMAN COLLEGE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7434722
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affect; African American; Algorithms; Benzimidazoles; Binding; Biological; Biological Factors; Caucasians; Caucasoid Race; Cell Proliferation; Cholesterol; Development; Diagnosis; Diet; Disseminated Malignant Neoplasm; Drug Design; Goals; Libraries; Ligands; Link; Malignant neoplasm of prostate; Mediating; Metabolism; Modeling; Numbers; Pathway interactions; Phosphorylation; Prevalence; Prostate Cancer therapy; Protein Overexpression; Proteins; Proto-Oncogene Proteins c-akt; Quantitative Structure-Activity Relationship; Regulation; Reporting; Research; Signal Pathway; Staging; Testing; Toxic effect; Work; absorption; analog; base; benzimidazole; cancer cell; caveolin 1; comparative; design; inhibitor/antagonist; novel; phosphoinositide-dependent kinase 1; prevent; programs; social; tumor

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.

Pi研究计划的长期目标是评估 苯并咪唑分子与该分子抑制PDK 1活性和PDK 1介导的能力有关 细胞增殖非裔美国人前列腺癌的差异归因于一些 社会和生物因素。已经注意到，富含胆固醇的饮食与过度肥胖有关。 cavoelin-1在诊断为前列腺癌的非裔美国人中的表达。Cavelin-1增强了 磷酸肌醇依赖性激酶1（PDK 1）的活性，磷酸肌醇3- 激酶/蛋白激酶B（PISK/Akt）信号通路。这种途径的成分的过度表达 有助于许多肿瘤的进展和发展。因此，PDK 1一直处于中心地位， 前列腺癌治疗的药物设计策略。然而，对影响的比较分析表明， 在非裔美国人和高加索人中尚未报道过此类药物。因此，本研究旨在 评估所提出的化合物库，以确定对PDK 1调节的影响。很有可能， 可以分析分子和PDK 1的结合相互作用，并且可以检验假设， 基于苯并咪唑的分子将有效地抑制PDK 1并防止PDK 1依赖性增殖。 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 为了验证这一假设，我们进行了以下工作：（1）合成一组苯并咪唑分子。(2)分析 分子的生物活性。将评估合成的分子抑制 细胞增殖、PDK 1中的ATP结合和PDK 1依赖性磷酸化。(3)确定 吸收、分布、代谢、消除和毒性（ADMETox）和定量构效关系 关系（QSAR）。该项目的成功完成应该表明，分子能够 阻止ATP与PDK 1结合以及随后Akt的磷酸化。这种活动应显示 该分子的潜力，以规避水平升高的小窝蛋白-1在非洲裔美国人，这导致 增加PDK 1活性。这一工作将有助于设计抗前列腺癌的有效分子 n非裔美国人。