Proof of concept molecules and molecular probes in drug discovery

本提案描述了我们实验室在设计化学探针和优化概念证明（PoC）分子方面计划或正在进行的几个项目，用于疾病靶点发现、验证和药物发现。一个相关的项目，以开发新的方法对映选择性合成，以促进先导优化也提出了。1)白三烯（LTs）与许多疾病有关，最近被认为在心血管疾病的炎症成分中起重要作用。LT生物合成抑制剂的副作用限制了它们的使用。最近发现了一类新的白三烯生物合成“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。我们计划制作亲和探针来识别细胞中这些化合物的分子靶标。鉴定将有助于更好地了解LT生物合成的机制和控制的基本细节，以及这类抑制剂作为新疗法的潜力。这项研究还将提供必要的分析工具来优化这些抑制剂，以确定可行的开发化合物。2)由于许多LT抑制剂类化合物的活性与季芳基手性中心的单一对映体相关，我们计划开发新的通用方法，直接合成基于新型手性硅二胺和氨基硅氧烷介导的正交金属化分子。这种方法在有机合成中具有广泛的适用性。3)丝氨酸-苏氨酸激酶是一大类高度同源的酶，参与许多细胞过程，并与多种疾病有关。选择性一直是这类抑制剂开发中的一个重要问题。我们计划开发工具来评估激酶表达（在正常和病变组织中）和细胞抑制的选择性。这些工具将基于亲和探针衍生的泛选择性激酶抑制剂staurosporine和类似物。这些工具将提供激酶表达图和酶占用分析，使药物发现和优化。

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.