Transition State Analogues as Modulators of DNA Methylation

作为 DNA 甲基化调节剂的过渡态类似物

基本信息

批准号：
8109261
负责人：
Vern L. Schramm
金额：
$ 26.19万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
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/8109261
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 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 Growth Head Head and Neck Cancer Head and neck structure Health 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 S-Adenosylhomocysteine S-Adenosylmethionine 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 response treatment effect tumor tumor growth

项目摘要

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'-甲硫腺苷磷酸化酶 (MTAP) 过渡态类似物抑制剂。 MTAP 抑制可减缓或阻止小鼠异种移植物中人类头颈癌、前列腺癌和人类肺癌的生长。正常组织不受影响，并且该抑制剂对正常细胞或小鼠没有毒性。 MTAP 抑制剂会改变代谢物，从而改变 DNA 甲基转移酶甲基化 DNA 的能力。癌症通常是由改变基因表达模式并允许肿瘤生长和转移的突变引起的。导致癌症的基因表达模式部分受到富含 CpG 碱基的基因组区域（称为 CpG 岛）的 DNA 甲基化的控制。这项研究的假设是 MTAP 抑制剂改变癌症组织中的代谢水平，从而抑制人类 DNA 甲基化模式。癌症抑制基因附近的一些 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，并减缓或阻止癌细胞生长。这一假设将在人类主要恶性肿瘤、肺癌、乳腺癌、前列腺癌、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。小鼠异种移植物中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人类癌症，并确定改变的基因表达模式。该假说还提出，CpG 岛 DNA 甲基化的抑制是通过 DNA 甲基转移酶介导的。对活体培养癌细胞、细胞提取物和纯化的人类 DNA 甲基转移酶复合物中的人类甲基转移酶的测定将与 DNA 甲基化模式和基因表达阵列相协调。将合成新的 MTAP 抑制剂以提高功效、口服利用度和化学稳定性。公共卫生相关性：人类癌症是由于作为细胞分裂调节因子的 DNA 区域失去控制而引起的。正在开发新的候选药物来恢复对这些细胞调节剂的正常控制。然后对这些药物进行测试，看看它们是否可以防止人类癌症在培养的人类细胞和小鼠体内生长。如果成功，这些研究可能会带来新的口服无毒药物来治疗人类癌症。