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。与加利福尼亚大学，伯克利大学和Rensselaer理工学院合作，建议通过其专有的“代谢稳定性” CHIP（或代谢酶稳定性芯片芯片芯片，或MESACHIPS candupt candupt）来满足药物安全技术的关键需求。正在开发Mesachip，以使制药行业用户能够模仿人肝脏的首次代谢。尽管近年来，新的化学实体数量（NCE）和可筛查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的数量增加，部分原因是由于NCE的毒性高于NCE或其代谢物（S）。药物安全评估的关键组成部分是候选药物的代谢稳定性，这反映了候选药物被代谢的敏感性和这种代谢的速度。但是，早期代谢稳定性分析目前受到可用方法固有的低吞吐量的限制，这些方法可提供准确的定量测量候选药物代谢。结果，缺乏早期高质量决策所需的准确信息。该阶段项目的具体目的是：1。开发基于良好的荧光测定法，从同时测量氧和NADPH消耗以及H2O2形成的同时测量中，可以确定P450催化的底物氧化速率。 2。使用LC-MS验证上述速率测量值可用于计算P450催化的氧化反应的准确速率。 3.在AIM 1中开发的固定板测定技术基于基于Metachip平台的高通量微阵列格式（Mesachip），该格式涉及在功能化的载玻片上掺入Microspots（<30 nl）中的P450。一旦完全开发，Mesachip将提供一个强大而高通量的技术平台，能够为药物研究人员提供预测候选药物的体内代谢稳定性所需的信息，从而有助于确定哪些化合物可以提出以进行铅优化。这种能力也是广泛采用个性化医学的关键先驱，可以预测药物代谢中的个体之间的差异，从而提供了有关单个患者水平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。药物发现过程是一种投资密集的高风险努力，可导致有效和安全的药物产量较低。通常，在预测候选药物的代谢命运以及预测人体中候选药物的反应性时，存在一个严重缺乏信息所困扰的问题。拟议的STTR开发项目用于开发Solidus Bioscience的Mesachip技术，通过向药物研究人员提供预测候选药物的体内代谢稳定性所需的信息，从而与公共卫生具有很大的相关性，从而有助于确定哪些化合物可以使哪些化合物提出来进行铅优化以及更好和安全的药物的最终开发。