Core 2: Medicinal Chemistry Core

核心 2：药物化学核心

基本信息

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
项目类别：
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

项目摘要

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.

项目概要令人信服的生物学数据表明 grp94（内质网 HSP90 旁系同源物）在该 PPG 的总体目标是促进恶性表型的进展和维持。对 grp94 的基本了解，最终目标是开发合理的基于 grp94 的分子因此，这三个综合项目的共同目标是揭示其机制。 grp94 的肿瘤作用背后，还提供了 grp94 如何发挥结构和生化作用的理解这些努力最终将导致人们了解如何最好地引入这些功能。用于治疗癌症的 grp94 抑制剂为了帮助这些努力，项目 2 将继续开发化学药物。有助于在整个 PPG 中进行机制研究的工具这些工具是选择性的、细胞的。可渗透的小分子配体，可用于及时阐明肿瘤细胞 grp94 的功能这些工具也是类药物 grp94 抑制剂，可在体内实现。研究 grp94 作为癌症靶点的潜力医学的总体目标。化学（核心2）是按照三个项目所需的数量和质量提供这些工具为了促进和促进拟议的 PPG 工作，核心 2 将产生一种时间和成本有效的方式。大量这些工具，以提供足够数量的 grp94 相关材料，以促进核心 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，制定适当的配方）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 研究人员。具体来说，Core 2 将： 1. 对所要求的 grp94 抑制剂和对照品进行放大合成和化合物表征四个项目所需的化合物（例如泛Hsp90抑制剂PU-H71）。 2. 对化合物进行配方和稳定性研究，目标是提供“即用型”工具体内研究（例如，体内研究制剂的制备、抑制剂库存的储存和处理）。 3. 对关键化合物进行特异性测试，探讨其对 grp94 的选择性并探究其潜力脱靶相关毒性（例如，在“脱靶”和“毒性”小组中进行筛选，例如 Caliper LifeSciences 的一般副作用概况 II (GEN SEP II) 和 Ambit 的激酶筛选）。 4. 对选定化合物进行体内 DMPK 研究（即 PK、肿瘤 PD、初步毒性和功效）项目 2 的结果是为 PPG 研究人员提供有关正确体内使用的信息（例如剂量和剂量）体内研究时间表、给药途径）。 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、衍生化的grp94抑制剂） grp94 配体，例如固体支持固定化抑制剂）和对照化合物（即泛 HSP90 抑制剂PU-H71）用于三个项目。意义：Core 2 是所有项目的接口实体，它拥有丰富的资源和专业知识。旨在为明智、及时完成拟议的 PPG 工作提供独特的资源。