Development of Nucleolin targeted Anticancer Compounds

描述（由申请人提供）：GRO 26 B和GRO 29 A是G-四联体形成适体寡核苷酸，其在体外和体内对癌细胞具有有效的抗增殖活性。GRO 26 B已经进入I期临床试验。它们对多种肿瘤类型（包括肺癌，前列腺癌，乳腺癌和结肠癌）具有活性，并且对恶性细胞具有高度选择性。这些适体的分子靶标已被鉴定为核仁素，一种在癌细胞的核仁和质膜中高度表达的多功能磷蛋白。在许多肿瘤类型中，高水平的核仁素表达预示着快速的肿瘤生长速度和不良的预后，这一点已经得到了很好的证实。核仁素位于肿瘤细胞的表面，而不是正常细胞的表面，我们已经证明，选择性靶向核仁素的分子比正常细胞更优先进入肿瘤细胞。因此，核仁素是癌症选择性靶标，靶向分子通过不进入正常细胞而潜在地具有较低的副作用和毒性。我们正在进行跨学科的方法来发现新的小分子靶向核仁素。初步数据表明，靶向核仁素的分子（例如，GRO 26 B和我们已经使用我们的方法鉴定的小分子）也可以表现出对癌细胞的生长抑制活性，而不影响正常细胞。我们建议，在了解GRO和小分子如何与核仁素结合时，我们可以使用基于结构的药物设计来产生新的小分子，这些小分子比基于阿托伐他汀的治疗具有更高的疗效。具体来说，我们需要了解GRO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素的复合物，以确定有利的特定相互作用。我们将针对这些区域筛选新的化合物，随后将测试其抗癌作用。本研究的意义在于，我们可以建立一类新的以核仁素为靶点的低毒小分子抗癌药物。

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.