Design and Development of Inhibitors of Methionine Adenosyltransferase for Cancer Treatment

用于癌症治疗的蛋氨酸腺苷转移酶抑制剂的设计和开发

• 批准号: 9899959
• 负责人: Courtney Nicole Niland
• 金额: $ 5.05万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2021-01-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899959
• 关键词: ATP Synthesis Pathway; Active Sites; Adenosine; Affinity; Alkynes; Azides; Binding; Binding Sites; Cancer Cell Growth; Cancer cell line; Cell Culture Techniques; Cell Line; Cell Survival; Cells; Chemistry; Complex; Crystallization; Dependence; Development; Drug Design; Electrostatics; Enzyme Inhibitor Drugs; Enzymes; Epigenetic Process; Event; Gene Amplification; Gene Deletion; Gene Expression; Generations; Genotype; Geometry; Goals; Human; In Situ; Isoenzymes; Isotopes; Kinetics; Laboratories; Libraries; Malignant Neoplasms; Measures; Metabolism; Methionine; Methionine Metabolism Pathway; Methods; Methylation; Modification; Monitor; Mus; Oncogenes; Pathway interactions; Phenotype; Phosphorylases; Polyamines; Predisposition; Protein Isoforms; Reaction; Reporting; Resistance; S-Adenosylmethionine; Site; Specificity; Structure; Testing; Thermodynamics; Time; Tissues; Treatment Efficacy; Triazoles; Work; Xenograft procedure; analog; anti-cancer; cancer cell; cancer therapy; cancer type; chemical synthesis; cycloaddition; design; enzyme structure; functional group; genomic locus; individualized medicine; inhibitor/antagonist; innovation; macromolecule; methionine adenosyltransferase; nanomolar; novel; overexpression; prevent; response; tumor progression; uptake

Project Abstract S-adenosyl-L-methionine (AdoMet) is a common methyl donor in cellular epigenetic modification of macromolecules to regulate gene expression. Methionine adenosyltransferase (MAT) is the sole enzyme responsible for AdoMet synthesis from ATP and methionine substrates. Three MAT isozymes are found in humans, with only the MAT2A isoform being expressed in most tissues and cancer cells. Over expression of MAT2A in cancer cells has been noted for some time. Recent studies have shown that a common gene deletion in cancer cells of 5’-methylthioadenosine phosphorylase (MTAP) creates susceptibility to MAT2A inhibition due to increased cellular dependence on AdoMet synthesis. Our lab has previously targeted MTAP using tight-binding transition state analogues that were successful in reducing cancer cell growth in cell culture and mouse xenografts. Cancer cells conditioned to MTAP inhibitor resistance were analyzed and a single gene amplification event at the MAT2A gene locus was identified. In this proposal, we will use two powerful methods of enzyme inhibitor design, click chemistry and transition state analogues, to target MAT2A. These innovative chemistry approaches have been applied to other enzyme targets to generate some of the tightest binding inhibitors known. Click chemistry and transition state analogue approaches allow for creation of bisubstrate analogues that target both the ATP and methionine binding sites of MAT2A. This simultaneous targeting of two enzyme active site groups increases the inhibitor affinity, as it resembles the short-lived but high-affinity intermediate reaction species. Inhibitors generated through these methods will be subject to structural, thermodynamic, and kinetic analysis. Efficacy of these high affinity MAT2A inhibitors on reducing cancer cell growth and viability will be analyzed on MTAP-/- and MTAP+/+ cancer cell lines. Co-treatment of cancer cell lines with MTAP transition state analogues will explore synergistic effects of MTAP and MAT2A. We hypothesize that MAT2A inhibitors generated from this work will amplify the anti-cancer effects MTAP inhibitors and provide a novel treatment for MTAP-/- cancers.

项目摘要 S-腺苷-L-甲硫氨酸（ADOMET）是细胞表观遗传修饰中的常见甲基供体 大分子调节基因表达。蛋氨酸腺基转移酶（MAT）是 唯一负责ATP和Methodine底物的ADOMEN合成的唯一酶。三个垫子 同工酶在人类中发现，只有MAT2A同工型在大多数组织中表达 和癌细胞。一段时间以来，已经注意到MAT2A在癌细胞中的表达过多。最近的 研究表明，5'-甲基硫代腺苷的癌细胞中的常见基因缺失 磷酸化酶（MTAP）由于细胞增加而产生对MAT2A抑制的敏感性 对Adomet合成的依赖。我们的实验室以前使用紧密结合对MTAP进行了瞄准 在降低细胞培养中癌细胞生长和成功的过渡状态类似物和 鼠标Xenographictics。分析了以MTAP抑制剂抗性为条件的癌细胞，并 鉴定了MAT2A基因基因座的单基因扩增事件。在此提案中，我们将 使用两种强大的酶抑制剂设计方法，单击化学和过渡状态 类似物，靶向MAT2A。这些创新的化学方法已应用于其他 酶靶标生成已知的一些最紧密的结合抑制剂。点击化学和 过渡状态模拟方法允许创建针对两个针对的双基层类似物 MAT2A的ATP和蛋氨酸结合位点。这两个酶的简单靶向 活跃的位点组增加了抑制剂的亲和力，因为它类似于短期但高亲和力 中间反应物种。通过这些方法产生的抑制剂将受到 结构，热力学和动力学分析。这些高亲和力MAT2A抑制剂的功效 关于降低癌细胞生长和生存能力，将在MTAP - / - 和MTAP+/+癌细胞上分析 线。癌细胞系与MTAP过渡状态类似物的共同处理将探索 MTAP和MAT2A的协同作用。我们假设MAT2A抑制剂是由 这项工作将扩大抗癌作用MTAP抑制剂，并为 MTAP - / - 癌症。