Inhibitors of Human Pal mitoyl Acyltransferase

人棕榈酰基转移酶抑制剂

• 批准号: 6831071
• 负责人: Charles E Ducker
• 金额: $ 34.89万
• 依托单位: APOGEE BIOTECHNOLOGY CORPORATION
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6831071
• 关键词: RNA interference; acyltransferase; antineoplastics; enzyme activity; enzyme inhibitors; fatty acylation; high performance liquid chromatography; high throughput technology; laboratory mouse; mass spectrometry; nuclear magnetic resonance spectroscopy; oncoproteins; palmitates; pharmacokinetics; prenylation; small molecule; technology /technique development

DESCRIPTION (provided by applicant): The goal of this program is to develop novel inhibitors of human palmitoyl acyltransferases (PATs) that are effective as cancer therapeutic agents. PATs represent new targets for anticancer drug development because of their pivotal roles in regulating the subcellular localization of specific oncoproteins. Most importantly, certain forms of ras-encoded proteins require palmitoylation for their targeting to the plasma membrane and for their ability to transform cells. Since post-translational processing of Ras proteins is critical for their function, the enzymes that catalyze these processing steps have been considered as potential targets for anticancer drugs. Inhibition of farnesylation has been the main focus of this therapeutic effort to date. However, the PATs may be even better targets, since palmitoylation is a dynamic process whereas farnesylation is not. A major reason that inhibition of palmitoylation has not yet been therapeutically exploited is that mammalian PATs have yet to be molecularly and biochemically characterized. Recent studies of palmitoylation in the yeast Saccharomyces cerevisiae have identified two putative PATs. Using the sequences of the yeast enzymes, we performed a search for homologues in vertebrates. Based on sequence and structural homologies, we selected a human protein called HIP3 for further study, i.e. to determine if this protein is an authentic human PAT (hPAT). Using RNA interference, we have shown that HIP3 has PAT activity, and that it affects the subcellular localization of palmitoylated proteins. In this SBIR program, these findings and our previously published work on hPATs will be used to develop small molecule inhibitors of hPATs to be evaluated as anticancer therapeutics. The following specific aims will be addressed in the Phase I project: 1. To identify compounds that inhibit hPAT activity by screening a diverse collection of small molecules in an established ass ay and a high-throughput yeast-based assay. 2. To use computational and medicinal chemistry to optimize these compounds. 3. To determine the in vitro activity, in vivo toxicity, pharmacokinetics and antitumor activity of lead PAT inhibitors.

描述（由申请人提供）：该项目的目标是开发新型的人棕榈酰酰基转移酶（PAT）抑制剂，其可有效用作癌症治疗剂。 PAT代表抗癌药物开发的新靶点，因为它们在调节特定癌蛋白的亚细胞定位中起关键作用。 最重要的是，某些形式的ras编码的蛋白质需要棕榈酰化，以使其靶向质膜和转化细胞的能力。 由于Ras蛋白的翻译后加工对其功能至关重要，催化这些加工步骤的酶已被认为是抗癌药物的潜在靶点。 迄今为止，法尼基化的抑制一直是这种治疗努力的主要焦点。 然而，PAT可能是更好的靶点，因为棕榈酰化是一个动态过程，而法尼基化不是。 棕榈酰化的抑制尚未在治疗上被利用的主要原因是哺乳动物PAT尚未被分子和生物化学表征。 最近的研究棕榈酰化的酵母酿酒酵母已经确定了两个假定的PAT。 利用酵母酶的序列，我们在脊椎动物中搜索同源物。 基于序列和结构同源性，我们选择了一种名为HIP 3的人类蛋白质进行进一步研究，即确定该蛋白质是否是真正的人类PAT（hPAT）。 使用RNA干扰，我们已经表明，HIP3具有PAT活性，并且它影响棕榈酰化蛋白质的亚细胞定位。 在这个SBIR计划中，这些发现和我们之前发表的关于hPATs的工作将用于开发hPATs的小分子抑制剂，以作为抗癌疗法进行评估。 第一阶段项目将实现以下具体目标： 1.通过在已建立的方法和基于酵母的高通量测定中筛选不同的小分子集合来鉴定抑制hPAT活性的化合物。 2.利用计算化学和药物化学来优化这些化合物。 3.目的：测定PAT先导抑制剂的体外活性、体内毒性、药代动力学和抗肿瘤活性。