Mechanism and Anti-Cancer Activity of SCFA-Hexosamine Analogs

描述(由申请人提供)：本申请继续研究以先导化合物Bu4ManNAc为代表的短链脂肪酸-N-乙酰甘露糖胺(SCFA-ManNAc)类似物。这种杂化分子从其正丁酸酯(Bu)基团获得HDACi生长抑制活性，并通过唾液酸生物合成途径增加代谢通量，这是由于酯酶完全去除正丁酸酯后产生的ManNAc。在该项目的最初资助期，人们发现Bu4ManNAc的部分水解产物(例如3，4，6-O-Bu3ManNAc)具有第三种活性模式，以亚细胞毒性剂量抑制转移性乳腺癌细胞的侵袭潜力。由于抗转移疗法的临床需求在很大程度上没有得到满足和迫切，第二个资助期将通过重点研究类似物抑制核因子-kB(目标1)和改变糖基化(目标2)的能力来研究这种新发现的抗癌活性背后的机制；同时，目前对细胞分析的重视将过渡到动物水平的测试(目标3)。更详细地，具体目标1将调查假设，SCFA-ManNAc类似物的子集的新的抗癌特性是通过(至少部分地)直接与NFKB1等途径元件结合而抑制核因子-kB的结果；这项研究的辅助目的是发现或设计更高效和更有效的类似物用于动物试验。在具体目标2中，将使用质谱学和生物信息学策略对模拟处理的细胞进行糖组学分析；这项工作将为体内模拟代谢的药代动力学追踪提供一种方法，并将从机制上深入了解多糖在转移中的作用。最后，特殊目标3将把这一项目转化为在啮齿动物身上的动物试验，以确定口服可利用度、安全性、药代动力学特性和器官分布，以及在转移癌症模型中的疗效。总之，这些实验将大大推进SCFA-ManNAc类似物的机械和翻译前景，SCFA-ManNAc类似物是一类新兴的糖基抗癌药物候选药物。 与公共卫生相关：该项目的最终目标是开发一种新的糖基抗癌药物来治疗转移性癌症。鉴于目前几乎所有类型的高度恶性疾病都缺乏有效的治疗药物，再加上每年新增数十万癌症病例，显然对正在开发的候选药物有着迫切的公共卫生需求。该项目旨在推动这一新兴疗法类别的测试，从基于细胞的分析到啮齿动物模型，这将反过来为转化为人类临床测试奠定基础。

DESCRIPTION (provided by applicant): This application continues the investigation of short chain fatty acid-N-acetylmannosamine (SCFA-ManNAc) analogs represented by the lead compound Bu4ManNAc. This hybrid molecule derives HDACi growth inhibitory activity from its n-butyrate (Bu) groups and increases metabolic flux through the sialic acid biosynthetic pathway due to ManNAc generated after complete removal of n-butyrate by esterases. During the initial funding period of this project, it was discovered that partial hydrolysis products of Bu4ManNAc (e.g., 3,4,6-O-Bu3ManNAc) have a third mode of activity that suppresses the invasive potential of metastatic breast cancer cells at subcytotoxic doses. Because of the largely unmet and urgent clinical need for anti-metastatic therapeutics, the second funding period will investigate the mechanism underlying this newly found anti-cancer activity by focusing on the ability of the analogs to inhibit NF-kB (Aim 1) and alter glycosylation (Aim 2); in tandem, the current emphasis on cell-based assays will be transitioned into animal-level testing (Aim 3). In more detail, Specific Aim 1 will investigate the hypothesis that novel anti-cancer properties of a subset of SCFA-ManNAc analogs are a consequence of NF-kB inhibition through (at least in part) direct binding to pathway elements such as NFKB1; an auxiliary purpose of this investigation is to discover or design more highly and efficacious analogs for animal testing. In Specific Aim 2, mass spectrometry and bioinformatics strategies will be used to conduct a glycomics analysis of analog-treated cells; this work will provide a method for pharmacokinetic tracking of analog metabolism in vivo and will also shed mechanistic insights into the role of glycans in metastasis. Finally, Specific Aim 3 will transition this project into animal testing in rodents to determine oral availability, safety, pharmacokinetic properties and organ distribution, and efficacy in metastatic cancer models. Together, these experiments will substantially advance both the mechanistic and translational prospects for SCFA-ManNAc analogs, an emerging class of sugar-based cancer drug candidates. PUBLIC HEALTH RELEVANCE: The ultimate goal of this project is to develop a new class of sugar-based cancer drugs to treat metastatic cancer. Based on the current lack of effective therapeutic agents for virtually all types of highly malignant disease, combined with the hundreds of thousands of new cases of cancer annually, there is clearly an urgent public health need for the drug candidates under development. This project is designed to propel the testing of this emerging class of therapeutics from cell-based assays to rodent models, which will in turn set the stage for translation to clinical testing in humans.