Novel Tool Compounds for Chromatin Research

描述（由申请人提供）：1期STTR提案旨在鉴定和开发靶向染色质调节蛋白的新型化合物。基于酵母的测定将用于筛选国家癌症研究所多样性集小分子文库。该检测试剂盒由确定的酵母突变体或报告菌株组成，其活力取决于许多染色质调节功能之一。特异性靶向这些功能的化合物引起突变株的生长抑制，但不引起相应野生型的生长抑制。该提案有三个部分。在目标1中，将使用多样性集进行基于新型报告菌株的两次筛选，以鉴定染色质功能的新抑制剂。在目标2中，已经进行的初步筛选的先导化合物将根据其对组蛋白乙酰转移酶活性的体外和体内作用来表征。目标3将致力于开发一组七种酵母和哺乳动物重组HAT酶，用于测试筛选得到的化合物的特异性功能。拟议的工作将有助于两个欠发达地区。首先，它将为染色质调控的研究提供新的和有价值的试剂。除了组蛋白去乙酰化酶抑制剂（HDAC）外，靶向特定染色质相关途径和活性的药物不可用。其次，这里提供的初步数据显示了基于酵母的技术快速识别染色质调节抑制剂的概念验证。这两个领域将是该项目未来发展的主要方向。

DESCRIPTION (provided by applicant): A Phase 1 STTR proposal seeks to identify and develop novel compounds that target chromatin regulatory proteins. A yeast-based assay will be used to screen the National Cancer Institute Diversity Set library of small molecules. The assay consists of defined yeast mutants or reporter strains whose viability depends on one of a number of chromatin-regulatory functions. Compounds that specifically target those functions cause growth inhibition of the mutant strain but not the corresponding wild-type. There are three parts to the proposal. In Aim 1, two screens based on novel reporter strains will be carried out with the Diversity Set in order to identify new inhibitors of chromatin function. In Aim 2, a lead compound from a preliminary screen already conducted wilt be characterized in terms of its effect on histone acetyltransferase activity in vitro and in vivo. Aim 3 will be devoted to developing a panel of seven yeast and mammalian recombinant HAT enzymes that will be used to test the specific functions of the compounds derived from the screens. The proposed work will contribute to two underdeveloped areas. First it will provide new and valuable reagents for the study of chromatin regulation. With the exception of the histone deacetylase inhibitors (HDACs), drugs that target specific chromatin-related pathways and activities are not available. Second, the preliminary data presented here shows proof-of-concept for the yeast-based technology to rapidly identify chromatin regulation inhibitors. These two areas will be the main thrust of the future development of this project.