Transition State Analogues as Modulators of DNA Methylation

作为 DNA 甲基化调节剂的过渡态类似物

• 批准号: 7686190
• 负责人: Vern L. Schramm
• 金额: $ 27万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-11 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686190
• 关键词: A549; Adenocarcinoma; Affect; Age; Apoptosis; Biochemical; Biological Assay; Breast; Cancer Cell Growth; Cancer cell line; Cell Culture Techniques; Cell Extracts; Cell Line; Cell division; Cells; Cervical; Colo205; Colon; Colon Carcinoma; Colorectal Cancer; Complex; CpG Islands; Crystallography; Cultured Cells; Cytostatics; DNA; DNA Methylation; DNA Methylation Inhibition; DNA Methyltransferase; DNA Modification Methylases; Data; Dissociation; Dorsal; Enzymes; Epigenetic Process; Feedback; Fibroblasts; Frequencies; Gene Expression; Genes; Genome; Genus Cola; Growth; Head; Head and Neck Cancer; Head and neck structure; Hela Cells; Histology; Human; Immune; Implant; Isotopes; Kinetics; Lead; Libraries; Life; Link; Literature; Lung; MCF7 cell; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Malignant neoplasm of lung; Malignant neoplasm of prostate; Measures; Mediating; Messenger RNA; Metabolic; Methylation; Methyltransferase; Mus; Muscle Form Glycogen Phosphorylase; Mutation; Neck Cancer; Neoplasm Metastasis; Normal Cell; Normal tissue morphology; Oral; Oral Administration; PC3 cell line; Pattern; Pharmaceutical Preparations; Phosphorylases; Polyamines; Production; Promoter Regions; Prostate; Relative (related person); Research; Site; Structure; Technology; Testing; Tissues; Toxic effect; Transgenic Organisms; Tumor Suppression; Tumor Suppressor Genes; Tumor Tissue; Xenograft Model; Xenograft procedure; analog; base; cancer cell; cancer therapy; chemical stability; computational chemistry; cytotoxic; design; drug candidate; foot; frontier; genome-wide; human DNA; human disease; improved; inhibitor/antagonist; mRNA Expression; malignant breast neoplasm; mouse model; prevent; public health relevance; response; treatment effect; tumor; tumor growth

DESCRIPTION (provided by applicant): Transition state analogue design is a frontier technology for targeting specific enzymes in human disease. MT-DADMe-Immucillin-A is an orally available transition state analogue inhibitor for human 5'- methylthioadenosine phosphorylase (MTAP). MTAP inhibition slows or prevents the growth of human head and neck, prostate and human lung cancers in mouse xenografts. Normal tissues are not affected and the inhibitor shows no toxicity against normal cells or to mice. The MTAP inhibitor alters metabolites that are expected to change the ability of DNA methyltransferases to methylate DNA. Cancers are commonly caused by mutations that change gene expression patterns and permit the growth and metastases of tumors. Gene expression patterns leading to cancer are governed, in part, by DNA methylation at regions of the genome rich in CpG bases, called CpG islands. The hypothesis for this research is that MTAP inhibitors alter metabolite levels in cancer tissues to inhibit DNA methylation patterns in humans. Loss of methylation for some of the CpG islands near cancer suppression genes is proposed to alter the gene expression patterns of the cancer cells and to slow or prevent cancer cell growth. This hypothesis will be explored in cultured cell lines and mouse xenograft models of the major human malignancies, lung, breast, prostate colon, head and neck and cervical cancers. Results of tumor growth in mouse xenografts will determine if orally available MTAP inhibitors are effective at suppression of the major human cancers and will identify the altered gene expression patterns. The hypothesis also proposes that inhibition of DNA methylation at CpG islands is mediated through DNA methytransferases. Assays of the human methyltransferases in living cultured cancer cells, cell extracts and in purified complexes of human DNA methyltransferases will be coordinated with DNA methylation patterns and gene expression arrays. New MTAP inhibitors will be synthesized to improve efficacy, oral availability and chemical stability. PUBLIC HEALTH RELEVANCE:Human cancers result from loss of control of the DNA regions that act as regulators for cell division. New drug candidates are being developed to restore normal control to these cell regulators. The drugs are then tested to see if they prevent human cancers from growing in cultured human cells and in mice. If successful, these studies could lead to new orally available and non-toxic drugs to treat cancers in humans.

描述（由申请人提供）：过渡状态类似物设计是针对人类疾病中特定酶的前沿技术。MT-DADMe-Immucillin-A是一种口服的人5'-甲基硫代腺苷磷酸化酶（MTAP）过渡态类似抑制剂。抑制MTAP可减缓或阻止小鼠异种移植物中人类头颈部、前列腺和人类肺癌的生长。正常组织不受影响，抑制剂对正常细胞或小鼠没有毒性。MTAP抑制剂改变了代谢产物，这些代谢产物有望改变DNA甲基化酶对DNA甲基化的能力。癌症通常是由改变基因表达模式的突变引起的，这些突变允许肿瘤的生长和转移。导致癌症的基因表达模式在一定程度上是由基因组中富含CpG碱基的区域（称为CpG岛）的DNA甲基化控制的。本研究的假设是MTAP抑制剂改变癌症组织中的代谢物水平，从而抑制人类DNA甲基化模式。一些靠近抑癌基因的CpG岛的甲基化缺失被认为可以改变癌细胞的基因表达模式，从而减缓或阻止癌细胞的生长。这一假设将在人类主要恶性肿瘤、肺癌、乳腺癌、前列腺癌、结肠癌、头颈癌和宫颈癌的培养细胞系和小鼠异种移植模型中进行探索。小鼠异种移植物肿瘤生长的结果将确定口服MTAP抑制剂是否能有效抑制主要的人类癌症，并将确定改变的基因表达模式。该假说还提出，CpG岛的DNA甲基化抑制是通过DNA甲基转移酶介导的。人甲基转移酶在活培养癌细胞、细胞提取物和纯化的人DNA甲基转移酶复合物中的检测将与DNA甲基化模式和基因表达阵列相协调。将合成新的MTAP抑制剂，以提高疗效、口服利用度和化学稳定性。公共卫生相关性：人类癌症是由于失去对作为细胞分裂调节因子的DNA区域的控制而导致的。新的候选药物正在开发中，以恢复对这些细胞调节因子的正常控制。然后对这些药物进行测试，看它们是否能防止人类癌症在培养的人类细胞和老鼠体内生长。如果成功，这些研究可能会导致新的口服无毒药物来治疗人类癌症。