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）：细胞外信号调节的激酶1和2（ERK1/2）蛋白在许多类型的癌细胞的增殖和存活中起主要作用，包括乳腺癌，前列腺和结直肠癌。因此，寻找新的方法来专门抑制ERK蛋白可能会导致新的化学治疗剂的发展。 ERK蛋白包含两个假定的对接结构域，这些结构域对于调节ERK相互作用底物蛋白的特异性和效率很重要。我们假设小分子量化合物会干扰ERK对接结构域，将有选择地阻断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铅化合物。这些化合物将测试其有选择地抑制底物蛋白ERK特异性磷酸化的能力。表现出抑制活性的化合物将测试与ERK对接结构域区域的特异性结合以及在阻断ERK依赖性细胞增殖方面的有效性。在拟议的研究结束时，我们希望鉴定出与ERK对接结构域结合的几种化合物，并特别抑制ERK介导的磷酸化。然后，这些化合物将用于进一步开发用于治疗含有ERK活性升高的癌症的治疗剂。这些研究代表了开发化合物的新方法，该方法有选择地阻断参与癌细胞增殖的蛋白质的ERK激活。