Development of Nucleolin targeted Anticancer Compounds

核素靶向抗癌化合物的开发

• 批准号: 6907002
• 负责人: John O Trent
• 金额: $ 25.88万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6907002
• 关键词: analytical ultracentrifugation; antineoplastics; chemical binding; chemical stability; chemical structure function; conformation; drug design /synthesis /production; nuclear magnetic resonance spectroscopy; nuclear proteins; nucleolus; oligonucleotides; phosphoproteins; solubility; thermodynamics

DESCRIPTION (provided by applicant): GRO26B and GRO29A are G-quartet forming aptamer oligonucleotides that have potent antiproliferative activity against cancer cells in vitro and in vivo. GRO26B has already entered Phase I clinical trials. They are active against a diverse range of tumor types (including lung, prostate, breast, and colon cancers) and are highly selective for malignant cells. The molecular target for these aptamers has been identified as nucleolin, a multifunctional phosphoprotein that is highly expressed in the nucleoli and plasma membrane of cancer cells. It is already well established that high levels of nucleolin expression predict rapid tumor growth rate and poor prognosis in many tumor types. Nucleolin is on the surface of tumor cells and not on the surface of normal cells and we have shown that molecules selectively targeting it enter tumor cells preferentially over normal cells. Therefore nucleolin is a cancer selective target with targeted molecules potentially having lower side effects and toxicity by not entering normal cells. We are undertaking an interdisciplinary approach to the discovery of new small molecules targeting nucleolin. Preliminary data indicate that molecules targeting nucleolin (for example, GRO26B and small molecules that we have already identified using our approach) can also exhibit growth inhibitory activity against cancer cells while not effecting normal cells. We propose that in understanding how GROs and small molecules bind to nucleolin, we can use structure-based drug design to generate new small molecule that have increased efficacy over oligonucleotide-based therapy. Specifically, we need to understand the properties and structures of the GROs and how they are related. Using that information we can examine the complexes with nucleolin to identify specific interactions that are favorable. We will target these regions to screen for new compounds that will be subsequently tested for anticancer effects. The significance of this research is that we could establish a new class of low toxicity small molecule anticancer agents targeted to nucleolin.

描述（由申请人提供）：GRO26B和GRO29A是g -四重奏形成的适体寡核苷酸，在体外和体内对癌细胞具有有效的抗增殖活性。GRO26B已经进入I期临床试验。它们对多种类型的肿瘤（包括肺癌、前列腺癌、乳腺癌和结肠癌）都有活性，对恶性细胞有很高的选择性。这些适体的分子靶标已被确定为核蛋白，这是一种在癌细胞核仁和质膜中高度表达的多功能磷酸化蛋白。在许多肿瘤类型中，高水平的核仁蛋白表达预示着肿瘤的快速生长和不良预后。核仁蛋白在肿瘤细胞的表面而不是在正常细胞的表面我们已经证明分子选择性地靶向它进入肿瘤细胞比正常细胞更优先。因此，核蛋白是一种癌症选择性靶点，其靶向分子不进入正常细胞，潜在的副作用和毒性较低。我们正在采取跨学科的方法来发现新的靶向核蛋白的小分子。初步数据表明，靶向核蛋白的分子（例如，GRO26B和我们已经使用我们的方法确定的小分子）也可以对癌细胞表现出生长抑制活性，而不影响正常细胞。我们建议，在了解GROs和小分子如何与核蛋白结合时，我们可以使用基于结构的药物设计来产生新的小分子，这些小分子比基于寡核苷酸的治疗具有更高的疗效。具体来说，我们需要了解GROs的性质和结构以及它们之间的关系。利用这些信息，我们可以检查与核仁蛋白的配合物，以确定有利的特定相互作用。我们将以这些区域为目标，筛选新的化合物，随后进行抗癌效果测试。本研究的意义在于可以建立一类新的以核蛋白为靶点的低毒性小分子抗癌药物。