Development of Inhibitors of the DNA Methylation Process

DNA甲基化过程抑制剂的开发

• 批准号: 6793223
• 负责人: JUDY Anne MIKOVITS
• 金额: $ 25.1万
• 依托单位: EPIGENX PHARMACEUTICALS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-20 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6793223
• 关键词: 3T3 cells; AIDS related neoplasm /cancer; DNA methylation; HIV infections; antineoplastics; chemical registry /resource; cisplatin; combinatorial chemistry; drug discovery /isolation; drug resistance; drug screening /evaluation; inhibitor /antagonist; laboratory mouse; microarray technology; neoplasm /cancer pharmacology; pharmacokinetics; toxicology

DESCRIPTION (provided by applicant): There is now considerable evidence that DNA methylation, by silencing tumor suppressor and mis-match repair genes, has a major role in the causation and progression of cancer and is also involved in abnormal DNA methylation events following HIV (Human Immunodeficiency Virus) infection. In the past year, two primary mechanisms in epigenetic gene silencing, DNA methylation and chromatin remodeling have merged as an important new approach to cancer therapy and diagnostics. Unlike mutated genes, epigenetically silenced genes are intact and can be reactivated by drugs that target the methylation process. There is a great need for reversible, less toxic methylation inhibitors. The primary objective of this proposal is to develop lead compounds identified in a unique cell-based screen designed to identify inhibitors of the methylation process. The screening of two chemical diversity libraries totaling more than 50,000 compounds, conducted during the Phase I program, identified more than eight chemically distinct classes of methylation inhibitors. For the proposed Phase II work, we will undertake a comprehensive development program and pre-clinical evaluation of the most promising compound class(es). Lead candidates from this evaluation will be tested in animal tumor models and a cellular model of HIV infection. We will also evaluate the ability of our lead drug candidate(s) to reverse drug resistant properties of several important anticancer drugs in clinical use, including cisplatin in non-small cell lung cancer and colorectal cancer.

描述（由申请人提供）：现在有相当多的证据表明，DNA甲基化，通过沉默肿瘤抑制基因和错配修复基因，在癌症的病因和进展中起主要作用，并且还参与HIV（人类免疫缺陷病毒）感染后的异常DNA甲基化事件。在过去的一年中，表观遗传基因沉默的两个主要机制，DNA甲基化和染色质重塑已经合并为癌症治疗和诊断的重要新方法。与突变基因不同，表观遗传沉默基因是完整的，可以通过靶向甲基化过程的药物重新激活。 非常需要可逆的、毒性较小的甲基化抑制剂。该提案的主要目标是开发在独特的基于细胞的筛选中鉴定的先导化合物，该筛选旨在鉴定甲基化过程的抑制剂。在第一阶段计划期间进行的两个化学多样性文库的筛选总计超过50，000种化合物，鉴定了超过8种化学上不同的甲基化抑制剂。对于拟议的II期工作，我们将对最有前途的化合物类别进行全面的开发计划和临床前评价。将在动物肿瘤模型和HIV感染的细胞模型中对该评估的主要候选人进行测试。我们还将评估我们的主要候选药物逆转临床使用的几种重要抗癌药物的耐药性的能力，包括非小细胞肺癌和结直肠癌中的顺铂。