Transition State Analogues as Modulators of DNA Methylation

描述（由申请人提供）：过渡态类似物设计是靶向人类疾病中特定酶的前沿技术。MT-DADMe-Immucillin-A是人5 '-甲硫腺苷磷酸化酶（MTAP）的口服过渡态类似物抑制剂。MTAP抑制减缓或防止人头颈癌、前列腺癌和人肺癌在小鼠异种移植物中的生长。正常组织不受影响，抑制剂对正常细胞或小鼠无毒性。MTAP抑制剂改变预期改变DNA甲基转移酶甲基化DNA的能力的代谢物。癌症通常由改变基因表达模式并允许肿瘤生长和转移的突变引起。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（称为CpG岛）的DNA甲基化控制。这项研究的假设是MTAP抑制剂改变癌组织中的代谢物水平，以抑制人类的DNA甲基化模式。癌症抑制基因附近的一些CpG岛的甲基化缺失被提出来改变癌细胞的基因表达模式并减缓或阻止癌细胞生长。将在主要人类恶性肿瘤、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探索这一假设。小鼠异种移植物中肿瘤生长的结果将确定口服MTAP抑制剂是否有效抑制主要的人类癌症，并将鉴定改变的基因表达模式。该假说还提出，CpG岛上DNA甲基化的抑制是通过DNA甲基转移酶介导的。活的培养癌细胞、细胞提取物和纯化的人DNA甲基转移酶复合物中的人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。新的MTAP抑制剂将被合成以提高功效、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剂的DNA区域失控而引起的。正在开发新的候选药物，以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，看看它们是否能阻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癌症。

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.