Core 2: Medicinal Chemistry Core

项目摘要 令人信服的生物学数据表明，grp 94，内质网HSP 90蛋白，在 恶性表型的发展和维持。本PPG的总体目标是推进 对grp 94的基本认识，最终目标是开发合理的基于grp 94的分子生物学 治疗癌症的方法。因此，这三个综合项目的共同目标是揭示这些机制， 在grp 94的肿瘤作用背后，也提供了grp 94如何在结构和生物化学上的理解， 影响这些功能。这些努力最终将导致对如何最好地引入 用于治疗癌症的GRP 94抑制剂。为了帮助这些努力，项目2将继续开发化学品， 有助于在整个PPG中进行的机制研究的工具。这些工具是有选择性的，细胞 可用于阐明肿瘤细胞GRP 94在时间上的功能的可渗透的小分子配体， 浓度特异性方式。这些工具也是类药物grp 94抑制剂， 研究GRP 94作为癌症靶点的潜力。医药的总体目标 化学（核心2）是提供这些工具的数量和质量所需的三个项目， 一种节省时间和成本的方式。为了促进和推动拟议的PPG工作，核心2将产生 大量的这些工具，使足够数量的grp 94相关材料，以促进 提出了研究。核心2将对合成材料进行质量控制（即，验证选择性， 适当的结构和纯度），配制用于建议用途的试剂（例如，制定适当的公式 用于体内使用），并将材料连同处理和储存说明一起运送给PPG研究者。 具体而言，核心2将： 1.对要求的grp 94抑制剂和对照品进行放大合成和化合物表征 化合物（例如，pan-Hsp 90抑制剂PU-H71）。 2.对化合物进行配方和稳定性研究，目的是提供“即用型”工具， 体内研究（例如，用于体内研究的试剂的制备、抑制剂原料的储存和处理）。 3.对关键化合物进行特异性检测，以探测其对grp 94的选择性，并探讨其潜在的 脱靶相关毒性（例如，在“脱靶”和“毒性”面板中进行筛选， 一般副作用PROFILE II（GEN SEP II）和Ambit的激酶筛选）。 4.进行体内DMPK研究（即，PK、肿瘤PD、初步毒性和功效） 为PPG研究者提供关于适当体内使用的信息（例如，剂量和 体内研究的时间表、给药途径）。 5.根据要求提供grp 94化学工具（例如，用于体外和体内研究的grp 94抑制剂，衍生的 GRP 94配体如固相载体固定化的抑制剂）和对照化合物（即，泛热休克蛋白90 抑制剂PU-H71）。 意义核心2是所有项目的接口实体。它拥有广泛的资源和专业知识， 能够为明智和及时地完成拟议的PPG工作提供独特的资源。

PROJECT SUMMARY Convincing biological data indicate an important role for grp94, the endoplasmic reticulum HSP90 paralog, in the progression and maintenance of a malignant phenotype. The overall objective of this PPG is to advance the fundamental understanding of grp94 with the ultimate goal of developing rational grp94-based molecular therapeutics against cancer. Thus, the three integrated Projects collectively aim to unveil the mechanisms behind the tumor roles of grp94 and also provide a structural and biochemical understanding of how grp94 influences these functions. These efforts ultimately will result in an understanding of how best to introduce grp94 inhibitors for the treatment of cancers. To aid these efforts, Project 2 will continue to develop chemical tools that will facilitate the mechanistic studies conducted throughout the PPG. These tools are selective, cell permeable small molecule ligands that can be used to elucidate tumor-cell grp94 functions in a time- and concentration-specific manner. These tools also are drug-like grp94 inhibitors that will enable in vivo investigation of the potential of grp94 as a target in cancers. The overarching objective of the Medicinal Chemistry (Core 2) is to provide these tools in the amount and quality required by the three Projects in a time- and cost-effective manner. To catalyze and facilitate the proposed PPG efforts, Core 2 will generate large quantities of these tools to make sufficient amounts of grp94-related materials available to facilitate proposed the studies. Core 2 will perform quality control on the synthesized materials (i.e., verify selectivity, proper structure and purity), formulate the agent for the proposed use (e.g., make the appropriate formulation for in vivo use), and ship the materials to the PPG investigator with instructions for handling and storage. Specifically, Core 2 will: 1. Conduct scale-up syntheses and compound characterization for requested grp94 inhibitors and control compounds (e.g., the pan-Hsp90 inhibitor PU-H71) required by the four Projects. 2. Perform formulation and stability studies on compounds with the goal of delivering `ready-to-use' tools for in vivo studies (e.g., preparation of agents for in vivo studies, storage and handling of inhibitor stocks). 3. Perform specificity testing of key compounds to probe their selectivity for grp94 and inquire into potential off-target related toxicities (e.g., screening in “off-target” and “tox” panels such as Caliper LifeSciences' General Side Effect PROFILE II (GEN SEP II) and Ambit's kinase screens). 4. Conduct in vivo DMPK studies (i.e., PK, tumor PD, preliminary tox and efficacy) on select compounds resulting from Project 2 to provide PPG investigators with information on proper in vivo use (e.g., dose and schedule for in vivo studies, route of administration). 5. Provide upon request grp94 chemical tools (e.g., grp94 inhibitors for in vitro and in vivo studies, derivatized grp94 ligands such as solid-support immobilized inhibitors) and control compounds (i.e., pan-HSP90 inhibitor PU-H71) for the three Projects. Significance. Core 2 is the interfacing entity of all the projects. It has extensive resources and expertise and is positioned to provide unique resources for a judicious and timely completion of the proposed PPG efforts.