Development of Inhibitors of the DNA Methylation Process

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，在癌症的起因和进展中起主要作用，也参与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、DNA甲基化和染色质重塑两种主要机制已经融合为癌症治疗和诊断的重要新途径。与突变基因不同，表观遗传沉默基因是完整的，可以通过靶向甲基化过程的药物重新激活。

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.