Kinase Imaging

这个项目汇集了一个新的科学家团队，探索新的化学物质， 将能够对参与人类信号转导的激酶进行成像。这些化学物质 探索的方法包括a）系统性天然产物衍生化以优化递送药代动力学，B） 肽文库方法和c）设计细胞膜可渗透的肽底物（烯烃钉合， 肽嵌合体）。选择这些化学物质是因为每种化学物质都能产生膜 以高度特异性方式与细胞内靶标反应的可渗透小分子。我们将专注于 两个靶点，脂质激酶PI 3 K（磷酸肌醇3-激酶）和蛋白激酶AKT（PKB）。所述pi 3 k 在高达90%的人类癌症中，该途径被上调，导致细胞生长、细胞存活和 细胞迁移重要的是，PI 3 K途径是许多人的主要非冗余控制机制。 癌症相关过程，例如血管生成、凋亡、细胞存活、细胞迁移和细胞增殖。 通过控制这个关键的信号中心，它可以作为许多冗余上游的读出 细胞外和下游细胞内信号传导靶标，例如VEGFR（Avastin）、her 2/neu（Erbitux）或 PDGFR（格列卫）。具体目标如下：1）开发和验证基于PI 3 K的显像剂 对具有膜渗透性的生物碱的绿啶家族，由于它们的 共价修饰PI 3 K的ATP位点中的赖氨酸，2）开发和验证基于AKT的成像剂 膜可透过的肽或肽模拟物，其将被该激酶磷酸化 并由于电荷的变化而被捕获在细胞内，以及3）在小鼠中验证上述成像剂 胰腺导管腺癌（PDAC）模型。这些实验的具体目标是a） 验证成像测量并将其与金标准相关联，B）进行PDAC的治疗试验 测试新开发的成像剂作为生物标志物的效用的治疗，以及c）将它们应用于询问 关于PDAC中PI 3 K/AKT生物学的问题。

This project brings together a new team of established scientists to explore novel chemistries that ultimately will enable imaging of the kinases involved in signaling transduction in humans. The chemistries to be explored include a) systematic natural product derivatization to optimize delivery pharmacokinetics, b) peptide library approaches and c) the design of cell membrane permeable peptide substrates (olefin stapling, peptide chimera). These chemistries have been selected because each has been shown to yield membrane permeable small molecules that react with intracellular targets in a highly specific manner. We will focus on two targets, the lipid kinase PI3K (phosphoinositide 3-kinase) and the protein kinase AKT (PKB). The PI3K pathway is up-regulated in up to 90% of human cancers leading to enhanced cell growth, cell survival and cell migration. Importantly, the PI3K pathway is a primary, non-redundant controlling mechanism for many cancer related processes such as angiogenesis, apoptosis, cell survival, cell migration, and cell proliferation. By controlling this critical signaling center, it can serve as a read-out for many redundant upstream extracellular and downstream intracellular signaling targets, such as VEGFR (Avastin), her2/neu (Erbitux), or PDGFR (Gleevec). The specific aims are as follows: 1) Develop and validate imaging agents for PI3K based on the viridin family of alkaloids that are membrane permeable and which are trapped inside cells due their covalent modification of a lysine in ATP site of PI3K, 2) develop and validate imaging agents for AKT based on peptides or peptidomimetics that are membrane permeable, which will be phosphorylated by this kinase and trapped intracellulary due to a change in charge and 3) validate the above imaging agents in mouse models of pancreatic ductal adenocarcinoma (PDAC). The specific goals of these experiments are to a) validate imaging measurements and correlate them to gold standards, b) perform therapeutic trials of PDAC treatments to test the utility of the newly developed imaging agents as biomarkers and c) apply them to ask questions about PI3K/AKT biology in PDAC.