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）：过渡状态模拟设计是针对人类疾病特定酶的前沿技术。 MT-dadme-immucillin-A是人类5'-甲基噻吩并腺苷磷酸化酶（MTAP）的口服过渡状态抑制剂。 MTAP抑制作用会减慢或防止小鼠异种移植物中人头和颈部，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的毒性无毒性。 MTAP抑制剂改变了预期改变DNA甲基转移酶甲基化DNA的能力的代谢产物。癌症通常是由改变基因表达模式并允许肿瘤的生长和转移引起的。导致癌症的基因表达模式部分由富含CpG碱基的基因组区域的DNA甲基化控制，称为CpG岛。这项研究的假设是MTAP抑制剂改变了癌症组织中的代谢物水平，以抑制人类的DNA甲基化模式。提出了一些CpG岛附近抑制癌症基因的甲基化损失，以改变癌细胞的基因表达模式并减慢或预防癌细胞的生长。该假设将在人类主要恶性肿瘤，肺，乳房，前列腺结肠，头颈和宫颈癌的培养细胞系和小鼠异种移植模型中进行探讨。小鼠异种移植物中肿瘤生长的结果将确定口服可用的MTAP抑制剂是否有效抑制主要的人类癌症，并将确定基因表达模式改变。该假设还提出，通过DNA甲基转移酶介导DNA甲基化的抑制DNA甲基化。人类甲基转移酶在活培养的癌细胞，细胞提取物和人DNA甲基转移酶的纯化复合物中的测定将与DNA甲基化模式和基因表达阵列协调。新的MTAP抑制剂将合成以提高功效，口服可用性和化学稳定性。公共卫生相关性：人类癌症是由于失去了充当细胞分裂调节剂的DNA区域的控制而导致的。正在开发新的候选药物以恢复这些细胞调节剂的正常控制。然后测试这些药物，以查看它们是否防止人类癌症在培养的人类细胞和小鼠中生长。如果成功，这些研究可能会导致新的口服和无毒药物来治疗人类的癌症。