Full Project 2: Synthesis and MAPK Kinase Inhibitiory Activities in Vitro and In

完整项目 2：体外和体内的合成和 MAPK 激酶抑制活性

• 批准号: 7250611
• 负责人: Samuel R Denmeade
• 金额: $ 8.11万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7250611
• 关键词: analog; clinical research; hormone related neoplasm /cancer; neoplastic cell; prostate neoplasms

Prostate cancer is the most commonly diagnosed cancer in American men. In 2005, an estimated 230,900 new cases will be diagnosed. Although androgen ablation is highly effective palliative therapy, all men eventually relapse due to the presence of androgen independent prostate cancer cells within metastatic sites. Currently there is no therapy that effectively eliminates these androgen independent prostate cancer cells. Identification of the signal transduction pathways responsible for survival and proliferation of androgen independent prostate cancer cells is critical for rational drug development. In preliminary studies, imido-substituted 2-chloro-1,4-naphthoquinones have been identified, that are selective inhibitors of Mek-1. Over the past year approximately 75 napthoquinone analogs have been synthesized and tested for cytotoxicity against a panel of human prostate cancer cell lines. These studies have identified certain structure-cytotoxicity relationships that will be exploited in synthesis of additional analogs. The goal of the studies is to identify potent cytotoxic imido-substituted napthoquinones that will be analyzed for inhibitory activity against MEK-1 and other membrane bound and intracellular protein kinases.

前列腺癌是美国男性中最常见的癌症。2005年，估计 新增确诊病例23.09万例。虽然雄激素消融是非常有效的姑息治疗，所有男性 最终由于转移部位内存在雄激素非依赖性前列腺癌细胞而复发。 目前还没有有效消除这些雄激素非依赖性前列腺癌细胞的疗法。 雄激素存活和增殖的信号转导通路的鉴定 独立的前列腺癌细胞对于合理的药物开发至关重要。在初步研究中，亚氨基取代的 2-氯-1，4-萘醌类化合物已被鉴定为Mek-1的选择性抑制剂。来 在过去的一年中，已经合成了大约75种萘醌类似物，并测试了其对一组 人前列腺癌细胞系。这些研究已经确定了某些结构-细胞毒性关系， 将用于合成其他类似物。研究的目的是鉴定有效的细胞毒性亚氨基取代的 萘醌类化合物将被分析对MEK-1和其他膜的抑制活性， 结合和细胞内蛋白激酶。