Target Identification of a Novel Antifungal Agent

描述（由申请人提供）：耐药和非敏感菌株的不断出现为继续寻找全新类别的抗真菌药物提供了令人信服的理由。Anacor Pharmaceuticals，Inc.发现了具有抗真菌活性的新型化合物（在某些情况下，对念珠菌属具有MIC）。< 1ug/ml。已证明该类成员在小鼠中具有良好的药代动力学和安全性。它们在真菌中的分子靶点尚不清楚。在这里，我们概述了一个简短的，集中的和高度集成的三盘建议，旨在发现这些新化合物的分子靶点。该过程将同时推进电极导线优化计划，以便在这些研究结束时，该项目将准备进入临床前开发活动。为了实现我们确定这些新化合物的目标，我们建议联合收割机结合三位高素质的主要研究者的专业知识和资源： 博士Jacob Planner，Anacor Pharmaceuticals（项目一：合成和药物化学） 博士Carolyn BellJnger-Kawahara，Anacor Pharmaceuticals（项目2：作用机制研究） 博士罗恩戴维斯，斯坦福大学基因组技术中心（项目三：化学基因组学） 目标1.1创建用于目标识别研究的工具化合物。 目标1.2领先扩张。 目标1.3效价优化。 目标2.1效价、光谱、细胞毒性 目标2.2大分子合成研究 Airn 2.3 De Novo阻力 目标2.4通过亲和方法识别目标 目标2.5试验开发 目标3.1化合物的预筛选 目的3.2全基因组筛选和验证（酵母属） 目的3.3念珠菌表达阵列 目标3.4数据获取和传播

DESCRIPTION (provided by applicant): The continual emergence of resistant and non-susceptible strains provides a compelling reason to continue the search for entirely new classes of antifungal drugs Anacor Pharmaceuticals, Inc has discovered novel compounds with antifungal activity (in some cases with MIC for Candida spp. < 1ug/ml. Members of this class have been shown to have favorable pharmacokinetics and safety in mice. Their molecular target in fungi is unknown. Here, we outline a short, focused and highly integrated three-pan proposal aimed at discovering the molecular target of these novel compounds. The process will simultaneously move forward the lead optimization program so that at the end of these studies, the project will be poised to enter preclinical development activities. To accomplish our goal of identifying the target of these novel compounds, we propose to combine the expertise and resources of three highly qualified principal investigators: Dr. Jacob Planner, Anacor Pharmaceuticals (Project One: Synthetic and Medicinal Chemistry) Dr. Carolyn BellJnger-Kawahara, Anacor Pharmaceuticals (Project Two: Mode of Action Studies) Dr. Ron Davis, Stanford Genome Technology Center (Project Three: Chemical Genornics) Aim 1.1 Creation of tool compounds for use in target identification studies. Aim 1.2 Lead expansion. Aim 1.3 Optimization of potency. Aim 2.1 Potency, Spectrum, Cytotoxicity Aim 2.2 Macromolecular Synthesis Studies Airn 2.3 De Novo Resistance Aim 2.4 Target Identification through Affinity Methods Aim 2.5 Assay Development Aim 3.1 Prescreening of compounds Aim 3.2 Whole genome screen and validation (Saccharomyces cerevisias) Aim 3.3 Candida Expression Array Aim 3.4 Data access and dissemination