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A High-Throughput Human Metabolic Stability Assay Chip for Early-Stage Drug Disco

用于早期药物迪斯科的高通量人体代谢稳定性检测芯片

基本信息

批准号：
7394070
负责人：
MOO-YEAL LEE
金额：
$ 20.06万
依托单位：
SOLIDUS BIOSCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-05 至 2010-02-04
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7394070
关键词：
Address Adoption Biological Assay California Catalysis Cells Chemicals Clinical Trials Combinatorial Synthesis Consumption Coupled Couples Cytochrome P450 Decision Making Development Devices Drug Delivery Systems Drug Formulations Drug Industry Drug Stability Environment Enzyme Stability Enzymes Evaluation Failure Fluorescence Glass Goals Human Human body Hydrogen Peroxide Individual Institutes Investments Lead Liver Measurement Medicine Metabolic Metabolism Methods NADP New Drug Approvals Numbers Optics Outcome Oxygen Patients Pharmaceutical Preparations Pharmacologic Substance Pharmacotherapy Phase Population Predisposition Preparation Process Productivity Protein Isoforms Public Health Rate Reaction Relative (related person)Research Research Personnel Risk Safety Science Screening procedure Slide Small Business Technology Transfer Research Speed Staging Subgroup System Techniques Technology Time Toxic effect Toxicology Translating Treatment Protocols United States National Institutes of Health Universities analog base design drug development drug discovery drug metabolism high throughput analysis high throughput technology in vivo oxidation programs tool

项目摘要

DESCRIPTION (provided by applicant): Solidus Biosciences, Inc. in partnership with the University of California, Berkeley, and Rensselaer Polytechnic Institute are proposing to address a critical need in drug safety technology through its proprietary "metabolic stability" chip (or Metabolizing Enzyme Stability Assay Chip, or MesaChip) for high-throughput analysis of drug candidate metabolism. The MesaChip is being developed to provide the pharmaceutical industry user with the ability to mimic the first-pass metabolism of the human liver. While in recent years there has been a dramatic increase in the number of new chemical entities (NCEs) and screenable drug targets, such increases in productivity have not translated into an increased number of new drug approvals, in part because of the high failure rate due to toxicity of the NCE or its metabolite(s). A critical component of drug safety evaluation is the metabolic stability of a drug candidate, which reflects the susceptibility of a drug candidate to be metabolized and the rate of such metabolism. Early stage metabolic stability analysis, however, is currently limited by the inherent low throughput of methods available that provide accurate quantitative measurement of drug candidate metabolism. As a result, accurate information required for early-stage high-quality decision making is lacking. The specific aims of this Phase I project are to: 1. Develop well-based fluorescence assays that enable determination of P450-catalyzed substrate oxidation rates from concurrent measurements of oxygen and NADPH consumption and of H2O2 formation. 2. Verify using LC-MS that the above rate measurements can be used to calculate accurate rates of P450-catalyzed oxidation reactions. 3. Adapt the well-plate assay techniques developed in Aim 1 to a high-throughput microarray format (MesaChip) based on the MetaChip platform that involves P450s incorporated into microspots (< 30 nL) on a functionalized glass slide. Once fully developed, the MesaChip will provide a robust and high-throughput technology platform capable of providing pharmaceutical researchers with the information needed to predict the in vivo metabolic stability of drug candidates, and thus help to decide which compounds are brought forward for lead optimization. This capability is also a critical precursor to the widespread adoption of personalized medicine, where differences among individuals in drug metabolism can be predicted, thereby providing information on the potential outcome of drug therapy at the individual patient level. The goals of this STTR project, therefore, fit the goals of the National Institutes of Health. The drug discovery process is an investment-intensive, high-risk endeavor that results in low yields of effective and safe drugs; a problem that is confounded by the significant lack of information that exists in predicting the metabolic fate of drug candidates, in general, and in predicting the reactivity of drug candidates in the human body. The proposed STTR project for the development of Solidus Bioscience's MesaChip technology has significant relevance to public health by providing pharmaceutical researchers with the information needed to predict the in vivo metabolic stability of drug candidates, and thus help to decide which compounds are brought forward for lead optimization and the ultimate development of better and safer drugs.

描述（由申请人提供）：Solidus Biosciences, Inc. 与加州大学伯克利分校和伦斯勒理工学院合作，提议通过其专有的“代谢稳定性”芯片（或代谢酶稳定性检测芯片，或 MesaChip）对候选药物代谢进行高通量分析，来满足药物安全技术的关键需求。 MesaChip 的开发旨在为制药行业用户提供模拟人类肝脏首过代谢的能力。尽管近年来新化学实体 (NCE) 和可筛选药物靶标的数量急剧增加，但生产率的提高并未转化为新药批准数量的增加，部分原因是 NCE 或其代谢物的毒性导致失败率较高。药物安全性评价的一个重要组成部分是候选药物的代谢稳定性，它反映了候选药物被代谢的敏感性以及代谢的速率。然而，早期代谢稳定性分析目前受到可提供候选药物代谢精确定量测量的方法固有的低通量的限制。因此，缺乏早期高质量决策所需的准确信息。该第一阶段项目的具体目标是： 1. 开发基础良好的荧光测定法，通过同时测量氧气和 NADPH 消耗以及 H2O2 形成来确定 P450 催化的底物氧化速率。 2. 使用 LC-MS 验证上述速率测量可用于计算 P450 催化氧化反应的准确速率。 3. 将目标 1 中开发的孔板测定技术改编为基于 MetaChip 平台的高通量微阵列格式 (MesaChip)，该平台涉及将 P450 合并到功能化玻璃载玻片上的微点 (< 30 nL) 中。一旦完全开发出来，MesaChip将提供一个强大的高通量技术平台，能够为药物研究人员提供预测候选药物体内代谢稳定性所需的信息，从而帮助决定哪些化合物需要进行先导化合物优化。这种能力也是广泛采用个性化医疗的重要先兆，可以预测个体之间药物代谢的差异，从而提供有关个体患者水平的药物治疗潜在结果的信息。因此，该 STTR 项目的目标符合美国国立卫生研究院的目标。药物发现过程是一项投资密集型、高风险的工作，导致有效且安全的药物产量低；总体而言，在预测候选药物的代谢命运以及预测候选药物在人体内的反应性方面，存在严重缺乏信息而造成的问题。拟议的 STTR 项目旨在开发 Solidus Bioscience 的 MesaChip 技术，它为药物研究人员提供了预测候选药物体内代谢稳定性所需的信息，从而有助于决定提出哪些化合物用于先导化合物优化以及最终开发更好、更安全的药物，从而与公共健康具有重大意义。