Mechanism and Anti-Cancer Activity of SCFA-Hexosamine Analogs

SCFA-己糖胺类似物的作用机制和抗癌活性

• 批准号: 8055985
• 负责人: Frederick J Krambeck
• 金额: $ 30.68万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8055985
• 关键词: Affect; Animal Testing; Animals; Antineoplastic Agents; Azides; Binding; Biochemical; Bioinformatics; Biological; Biological Assay; Breast Cancer Cell; Cancer Model; Cell Cycle Arrest; Cell Line; Cells; Clinical; Collaborations; Complement; Computer Simulation; Data; Development; Disease; Disseminated Malignant Neoplasm; Dose; Drug Kinetics; Elements; Esters; Excision; Funding; Glycoconjugates; Glycoproteins; Glycosphingolipids; Goals; Growth; HCT116 Cells; Hexosamines; Histone deacetylase inhibition; Human; Hybrids; Hydrolysis; Immunoprecipitation; Individual; Induction of Apoptosis; Investigation; Ketones; Label; Laboratories; Lead; Link; Malignant - descriptor; Malignant Neoplasms; Mass Spectrum Analysis; Matrix Metalloproteinases; Metabolic; Metabolic stress; Metabolism; Methods; Modeling; Molecular; Molecular Probes; Molecular Target; Monitor; Monosaccharides; Mucin-1 Staining Method; Mus; N-acetylmannosamine; NF-kappa B; Neoplasm Metastasis; Oral; Organ; Organism; Pathway interactions; Polysaccharides; Procedures; Process; Property; Proteins; Public Health; Qualifying; Research Project Grants; Rodent; Rodent Model; Role; Safety; Sampling; Sialic Acids; Signal Transduction; Site-Directed Mutagenesis; Small Interfering RNA; Software Tools; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Staging; Stimulus; Structure; Supplementation; Surface; Surface Plasmon Resonance; Testing; Therapeutic; Therapeutic Agents; Tissues; Translations; United States National Institutes of Health; Up-Regulation; Volatile Fatty Acids; Work; analog; base; cancer cell; design; drug candidate; esterase; glycosylation; in vivo; insight; n Butyrate; novel; public health relevance; research clinical testing; research study; response; scaffold; sugar

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.

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。这种混合分子从其正丁酸 (Bu) 基团中获得 HDACi 生长抑制活性，并通过酯酶完全去除正丁酸后生成的 ManNAc 来增加通过唾液酸生物合成途径的代谢通量。在该项目的初始资助期间，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在很大程度上未得到满足且紧迫，第二个资助期将通过关注类似物抑制 NF-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的机制；与此同时，目前对细胞检测的重视将转变为动物水平测试（目标 3）。更详细地说，具体目标 1 将研究这样的假设：SCFA-ManNAc 类似物子集的新抗癌特性是通过（至少部分）直接结合到 NFKB1 等通路元件来抑制 NF-kB 的结果；这项研究的一个辅助目的是发现或设计用于动物试验的更高效、更有效的类似物。在具体目标 2 中，将使用质谱和生物信息学策略对类似物处理的细胞进行糖组学分析；这项工作将为体内类似物代谢的药代动力学追踪提供一种方法，还将为聚糖在转移中的作用提供机制见解。最后，Specific Aim 3 将该项目转变为啮齿类动物试验，以确定口服有效性、安全性、药代动力学特性和器官分布，以及在转移性癌症模型中的疗效。总之，这些实验将极大地推进 SCFA-ManNAc 类似物（一类新兴的糖类癌症候选药物）的机制和转化前景。 公共健康相关性：该项目的最终目标是开发一类新型糖基癌症药物来治疗转移性癌症。由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，再加上每年有数十万新发癌症病例，显然公共卫生对正在开发的候选药物存在迫切需求。该项目旨在推动这一新兴疗法的测试，从基于细胞的测定到啮齿动物模型，这反过来又将为转化为人类临床测试奠定基础。