Development of ERK docking domain inhibitors

ERK对接域抑制剂的开发

• 批准号: 6719456
• 负责人: PAUL S SHAPIRO
• 金额: $ 13.37万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6719456
• 关键词: 3T3 cells; SDS polyacrylamide gel electrophoresis; antineoplastics; biological signal transduction; cell proliferation; drug discovery /isolation; enzyme activity; enzyme inhibitors; enzyme substrate; epidermal growth factor; fluorescence spectrometry; growth factor receptors; mitogen activated protein kinase; neoplastic transformation; phosphorylation; protein protein interaction; technology /technique development; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): The extracellular signal-regulated kinase-1 and 2 (ERK1/2) proteins play a major role in the proliferation and survival of many types of cancer cells, including breast, prostate, and colorectal carcinomas. Therefore, finding novel ways to specifically inhibit ERK proteins may lead to the development of new chemotherapeutic agents. ERK proteins contain two putative docking domains that are important for regulating the specificity and efficiency of ERK interacting substrate proteins. We hypothesize that small molecular weight compounds that interfere with ERK docking domains will selectively block ERK interactions with substrate proteins and inhibit cell proliferation. For these studies, we will use computer aided drug design (CADD) to identify potential lead compounds that interact with ERK docking domains. These compounds will be tested for their ability to selectively inhibit ERK-specific phosphorylation of substrate proteins. Compounds that show inhibitory activity will be tested for specific binding to the ERK docking domain regions and effectiveness in blocking ERK-dependent cell proliferation. At the end of the proposed studies, we expect to identify several compounds that bind to the ERK docking domains and specifically inhibit ERK-mediated phosphorylation. These compounds will then be used in further development of therapeutic agents for treating cancers containing elevated levels of ERK activity. These studies represent a novel approach for developing compounds that selectively block ERK activation of proteins involved in cancer cell proliferation.

描述（由申请人提供）：细胞外信号调节激酶1和2（ERK1/2）蛋白在许多类型的癌细胞（包括乳腺癌、前列腺癌和结直肠癌）的增殖和存活中发挥重要作用。因此，寻找特异性抑制 ERK 蛋白的新方法可能会导致新化疗药物的开发。 ERK 蛋白包含两个假定的对接结构域，这对于调节 ERK 相互作用底物蛋白的特异性和效率非常重要。我们假设干扰 ERK 对接域的小分子量化合物将选择性地阻断 ERK 与底物蛋白的相互作用并抑制细胞增殖。对于这些研究，我们将使用计算机辅助药物设计 (CADD) 来识别与 ERK 对接域相互作用的潜在先导化合物。将测试这些化合物选择性抑制底物蛋白 ERK 特异性磷酸化的能力。将测试表现出抑制活性的化合物与 ERK 对接结构域区域的特异性结合以及阻断 ERK 依赖性细胞增殖的有效性。在拟议的研究结束时，我们期望鉴定出几种与 ERK 对接结构域结合并特异性抑制 ERK 介导的磷酸化的化合物。这些化合物随后将用于进一步开发用于治疗 ERK 活性水平升高的癌症的治疗剂。这些研究代表了一种开发化合物的新方法，该化合物选择性地阻断参与癌细胞增殖的蛋白质的 ERK 激活。