Core 2: Medicinal Chemistry Core

核心 2：药物化学核心

• 批准号: 8934512
• 负责人: GABRIELA CHIOSIS
• 金额: $ 29.29万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8934512
• 关键词: Address; Adverse effects; Biochemical; Biological; Biological Availability; Biology; Cancer Biology; Cell model; Cells; Chemicals; Colon Carcinoma; Computing Methodologies; Data; Development; Dose; Drug Formulations; Endoplasmic Reticulum; Feedback; Goals; Heat-Shock Proteins 90; Housing; Human; In Vitro; Instruction; Investigation; Libraries; Ligands; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Molecular; Molecular Chaperones; Multiple Myeloma; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phosphotransferases; Positioning Attribute; Preparation; Quality Control; Research Personnel; Resources; Role; Route; Schedule; Scheme; Services; Shipping; Ships; Solid; Source; Specificity; Structure; Testing; Therapeutic; Time; Toxic effect; base; cancer therapy; catalyst; cost; cost effective; effective therapy; in vivo; inhibitor/antagonist; malignant breast neoplasm; malignant phenotype; neoplastic cell; novel; paralogous gene; scale up; screening; small molecule; tool; tumor

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.

项目摘要 令人信服的生物学数据表明GRP94的重要作用，内质网hsp90旁系同源物中 恶性表型的进展和维持。该PPG的总体目标是进步 对GRP94的基本理解的最终目的是开发基于理性的GRP94分子 针对癌症的治疗。这是三个集成的项目集体旨在揭示机制 GRP94肿瘤作用的背后，还提供了对GRP94的结构和生化理解 影响这些功能。这些努力最终将导致了解如何最好地介绍 用于治疗癌症的GRP94抑制剂。为了帮助这些努力，项目2将继续开发化学 将促进整个PPG进行的机械研究的工具。这些工具是选择性的，单元格 可渗透的小分子配体，可用于阐明时间和时间中的肿瘤细胞GRP94功能 浓度特异性的方式。这些工具也是类似药物的GRP94抑制剂，可以在体内实现 研究GRP94作为癌症的靶标的潜力。药用的总体目标 化学（Core 2）是为这些工具提供的三个项目所需的数量和质量 时间和成本效益的方式。为了催化和促进拟议的PPG工作，Core 2将产生 大量这些工具，以制造足够数量的GRP94相关材料，以促进 提出了研究。 Core 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），制定拟议用途的试剂（例如，制定适当的公式 用于体内使用），然后将材料运送到PPG调查员，并提供用于处理和存储的说明。 具体而言，核心2将： 1。对请求的GRP94抑制剂和对照的进行扩大合成和化合物表征 四个项目需要的化合物（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，为体内研究，抑制剂库存的存储和处理制备制备）。 3.对关键化合物进行特异性测试，以探测其对GRP94的选择性并询问潜在 非目标相关的毒性（例如，在“脱靶”和“托克斯”面板中进行筛选，例如卡尺寿命' 一般副作用曲线II（Gen Sep II）和Ambit的激酶筛选）。 4。在精选化合物上进行体内DMPK研究（即PK，PK，肿瘤PD，初步毒品和效率） 由项目2导致的，为PPG调查人员提供有关体内使用适当的信息（例如，剂量和剂量和 体内研究的时间表，管理途径）。 5。根据要求提供GRP94化学工具（例如，用于体外和体内研究的GRP94抑制剂，衍生化 GRP94配体，例如固定抑制剂）和对照化合物（即Pan-HSP90 抑制剂PU-H71）用于三个项目。 意义。核心2是所有项目的接口实体。它具有广泛的资源和专业知识，是 定位，可以为拟议的PPG工作明智而及时完成独特的资源。