Proof of concept molecules and molecular probes in drug discovery

该提案描述了我们实验室计划或正在进行的几个项目，涉及化学探针的设计和用于疾病靶点发现、验证和药物发现的优化概念验证（proof of concept，简称proof）分子。一个相关的项目，以开发新的方法对映体选择性合成，以促进铅优化。1)白三烯（LT）与许多疾病有关，最近被认为在心血管疾病的炎症组分中起重要作用。LT生物合成的抑制剂与限制其使用的副作用有关。最近发现了一类新的白细胞三烯生物合成“异常”抑制剂，其作用机制尚不清楚。这类优化的化合物可能表现出更好的慢性安全性和耐受性特征。我们计划制作亲和探针来鉴定细胞中这些化合物的分子靶标。 鉴定将允许更好地理解LT生物合成的机制和控制的基本细节以及作为新疗法的这一新类别中的抑制剂的潜力。这项研究还将提供必要的分析工具，以优化这些抑制剂，以确定可行的开发化合物。2)由于LT抑制剂类中的许多化合物具有与季芳基手性中心处的单一对映异构体相关的活性，因此我们计划开发基于新型手性甲硅烷基二胺和氨基硅氧烷介导的邻位定向金属化直接合成此类分子的新的通用方法。 这些方法在有机合成中具有广泛的适用性。3)丝氨酸-苏氨酸激酶形成参与许多细胞过程并与多种疾病有关的大的且高度同源的酶类别。选择性一直是此类抑制剂开发中的重要问题。我们计划开发工具来评估激酶表达（在正常和患病组织中）和细胞中抑制的选择性。这些工具将基于来自泛选择性激酶抑制剂星形孢菌素和类似物的亲和探针。这些工具将提供激酶表达图谱和酶占有率测定，以实现药物发现和优化。

This proposal describes several of the projects planned or ongoing in our labs on design of chemical probes and optimized proof of concept (PoC) molecules for disease target discovery, validation and drug discovery. An associated project to develop new methods for enantioselective synthesis to facilitate lead optimization is also presented. 1) Leukotrienes (LTs) are implicated in a number of diseases and more recently are postulated to play an important role in inflammatory components of cardiovascular diseases. Inhibitors of LT biosynthesis have been associated with adverse effects which limit their use. A new class of "anomalous" inhibitors of leukotriene biosynthesis has recently been discovered whose mechanism of action is not understood. Optimized compounds in this class may exhibit a better chronic safety and tolerability profile. We plan to make affinity probes to identify the molecular target(s) on these compounds in the cell. Identification will allow a better understanding of the fundamental details of mechanism and controls of LT biosynthesis and the potential of inhibitors in this new class as new therapies. This research will also provide the assay tools necessary to optimize such inhibitors to identify viable development compounds. 2) As many compounds in the class of LT inhibitors have activity associated with a single enantiomer at a quaternary aryl chiral center, we plan to develop new and versatile methods for direct synthesis of such molecules based on ortho-directed metalation mediated by novel chiral silyldiamines and aminosiloxanes. Such methods will have broad applicability in organic synthesis. 3) Serine-threonine kinases form a large and highly homologous class of enzymes involved in many cellular processes and implicated in a wide variety of diseases. Selectivity has been an important problem in the development of such inhibitors. We plan to develop tools to assess kinase expression (in normal and diseased tissue) and selectivity of inhibition in cells. These tools will be based on affinity probes derived from the pan-selective kinase inhibitor staurosporine and analogs. Such tools will provide kinase expression maps and enzyme occupancy assays to enable drug discovery and optimization.