Specific Inhibitors of Histone Deacetylases

组蛋白脱乙酰酶的特异性抑制剂

• 批准号: 6526122
• 负责人: SCOTT E LAZERWITH
• 金额: $ 3.78万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6526122
• 关键词: amidohydrolases; analog; binding sites; biotechnology; cell line; chemical structure function; chemical synthesis; drug design /synthesis /production; enzyme inhibitors; enzyme substrate complex; gene expression; gene mutation; histones; hydroxamate; protein isoforms; site directed mutagenesis

DESCRIPTION (provided by applicant) The research described in this application is a novel approach to the study of histone deacetylase enzymes (HDACs). These enzymes, which catalyze the removal of an acetyl group from the lysine residues of histone proteins, have recently been recognized to play an important role in the regulation of gene transcription, and have also been implicated in the suppression of some cancers. There are at least eight known human HDACs and five known yeast HDACs. Unfortunately, study of the specific targets and functions of the individual HDACs is hindered by a lack of selective inhibitors. The approach proposed involves engineering site-specific mutants of HDACs, thus creating molecular holes. Rationally designed inhibitors containing some extra steric bulk or "bumps" will then be synthesized to fit the mutant enzymes, thus creating specific inhibitors of individual HDACs. The engineered enzyme/inhibitor systems will then be inserted into cells to probe the effects of selective HDAC inhibition.

描述(由申请人提供) 本申请中描述的研究是一种研究 组蛋白脱乙酰酶(HDAC)。这些酶，催化脱除 来自组蛋白赖氨酸残基的乙酰基，最近 已被认为在基因调控中发挥着重要作用 转录，并且还被牵连到抑制一些 癌症。至少有8种已知的人类HDAC和5种已知的酵母HDAC。 不幸的是，对个体的具体目标和功能的研究 HDAC由于缺乏选择性抑制剂而受到阻碍。建议的方法 涉及改造HDAC的特定位点突变体，从而创建分子 洞穴。合理设计的抑制剂含有一些额外的空间体积或 “凸起”随后将被合成以适应突变酶，从而产生 个别HDAC的特定抑制剂。基因工程酶/抑制剂 然后系统将被插入细胞中，以探测选择性HDAC的影响 抑制力。