Core 2: Medicinal Chemistry Core

项目总结 令人信服的生物学数据表明，grp94，内质网HSP90类似物，在 恶性表型的进展和维持。这个PPG的总体目标是推进 对grp94的基本认识，最终目标是开发基于grp94的合理分子 癌症治疗学。因此，这三个综合项目的共同目标是揭示这些机制 并提供了对grp94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 用于癌症治疗的grp94抑制剂。为了帮助这些努力，项目2将继续开发化学物质 将促进在整个PPG中进行的机械学研究的工具。这些工具是有选择性的，细胞 可用于在一段时间内阐明肿瘤细胞grp94功能的渗透性小分子配体-和 特定于浓度的方式。这些工具也是类似药物的grp94抑制剂，将在体内使 研究grp94作为癌症靶点的可能性。《医学》的总体目标 化学(核心2)将提供这些工具，其数量和质量符合以下三个项目的要求 既省时又省钱的方式。为了催化和促进拟议的PPG努力，核心2将产生 大量使用这些工具，以提供足够数量的grp94相关材料，以便利 提出了研究建议。核心2将对合成材料执行质量控制(即，验证选择性， 适当的结构和纯度)，为建议的用途配制试剂(例如，制造适当的配方 供活体使用)，并将材料运往PPG调查员，并提供搬运和储存说明。 具体而言，酷睿2将： 1.对所要求的grp94抑制剂和对照进行放大合成和化合物表征 四个项目所需的化合物(例如，PAN-Hsp90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“现成”工具 体内研究(例如，体内研究试剂的制备、抑制剂库存的储存和处理)。 3.对关键化合物进行特异性试验，考察其对grp94的选择性，探讨其潜力 与靶外相关的毒性(例如，在“靶外”和“毒性”小组中进行筛查，如卡利珀生命科学公司的 一般副作用分析II(GEN SEP II)和安必特的激酶筛查)。 4.对选定的化合物进行体内DMPK研究(即PK、肿瘤PD、初步毒性和有效性) 由项目2产生，为PPG研究人员提供关于体内正确使用的信息(例如，剂量和 体内研究时间表，给药路线)。 5.应要求提供grp94化学工具(例如，用于体外和体内研究、衍生的grp94抑制剂 Grp94配体，例如固体载体固定化抑制剂)和对照化合物(即，PAN-HSP90 抑制剂PU-H71)用于这三个项目。 意义重大。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，并 能够为明智和及时完成拟议的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.