Development of Inhibitors of the DNA Methylation Process

描述(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，在癌症的发生和发展中发挥重要作用，并与HIV(人类免疫缺陷病毒)感染后的异常DNA甲基化事件有关。在过去的一年里，表观遗传基因沉默的两种主要机制--DNA甲基化和染色质重塑--已合并为癌症治疗和诊断的重要新途径。与突变基因不同，表观遗传沉默的基因是完整的，可以通过针对甲基化过程的药物重新激活。 非常需要可逆的、毒性较低的甲基化抑制剂。这项提议的主要目标是开发在一种独特的基于细胞的筛查中确定的先导化合物，旨在确定甲基化过程的抑制剂。在第一阶段计划期间，对总计50,000多种化合物的两个化学多样性文库进行了筛选，确定了八种以上化学上不同的甲基化抑制剂类别。对于拟议的第二阶段工作，我们将对最有希望的化合物类别进行全面的开发计划和临床前评估。这项评估的主要候选者将在动物肿瘤模型和艾滋病毒感染的细胞模型中进行测试。我们还将评估我们的主要候选药物S逆转临床使用的几种重要抗癌药物的耐药性的能力，包括用于非小细胞肺癌和结直肠癌的顺铂。

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.