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。该杂交分子通过其正丁酸（Bu）基团获得hdac的生长抑制活性，并通过酯酶完全去除正丁酸后产生的甘露聚糖（ManNAc）通过唾液酸生物合成途径增加代谢通量。在该项目的初始资助期内，研究人员发现，Bu4ManNAc的部分水解产物（例如3,4,6- o - bu3mannac）具有第三种活性模式，可以在亚细胞毒性剂量下抑制转移性乳腺癌细胞的侵袭潜力。由于抗转移治疗的临床需求很大程度上未得到满足和迫切，第二个资助期将通过关注类似物抑制NF-kB （Aim 1）和改变糖基化（Aim 2）的能力来研究这种新发现的抗癌活性的机制；同时，目前强调的基于细胞的检测将过渡到动物水平的测试（目标3）。更详细地说，Specific Aim 1将研究一种假设，即SCFA-ManNAc类似物子集的新型抗癌特性是NF-kB抑制的结果，通过（至少部分地）直接结合NFKB1等途径元件；本研究的一个辅助目的是发现或设计更高效的类似物用于动物试验。在Specific Aim 2中，质谱和生物信息学策略将用于对类似物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跟踪提供一种方法，并将揭示聚糖在转移中的作用机制。最后，Specific Aim 3将把该项目转化为啮齿动物试验，以确定口服有效性、安全性、药代动力学特性和器官分布，以及转移性癌症模型的有效性。总之，这些实验将极大地推进SCFA-ManNAc类似物的机制和翻译前景，这是一类新兴的糖基癌症候选药物。

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.