Performing ADMET Assays in Nanodroplets

描述（由申请人提供）：本提案的目标是开发一种完全集成的基于纳米液滴（nanodroplet）的电润湿（EW）装置，以加速药物发现过程，特别是吸附、分布、代谢、排泄和毒理学（ADMET）领域。传统上，药物发现是一个连续的过程，从治疗靶点识别/验证到初始（先导）化合物的初步筛选，再到效价的化学优化。这些步骤之后是ADMET评估、临床前/临床试验、生产和营销。最近的数据显示，由于ADMET性能差，80%的潜在药物被淘汰。这一观察引起了这一过程的巨大变化。生物制药行业现在正在寻找能够同时筛选化合物以获得最佳治疗效力和最有利的ADMET特性的技术。通过推广具有这种适当的“类药物”特性组合的化学先导物，预计药物开发将实现巨大的成本节约，并加速整个药物开发过程。在第一阶段，我们打算证明电子战对各种ADMET方法的适用性。几个简单的生化分析已经在我们的平台上进行了演示。然而，对于ADMET，通常采用更复杂的系统。因此，我们的研究将证明进行微粒体细胞色素P-450检测、贴壁和非贴壁细胞检测以及定量聚合酶链反应的能力。该系列协议将为第二阶段大量ADMET分析的整合提供实验基础。EW平台的生化通用性很有吸引力，就像EW的其他几个特性一样。通过只使用纳米液滴，与目前的方法相比，每次检测所需的试剂减少了约1000倍。因此，药物筛选过程中使用的珍贵化合物、靶蛋白和细胞系是保守的。此外，EW有助于同时快速执行多个检测方案。因此，在第二阶段，我们预计单个芯片每天产生超过100,000个数据点。与行业筛选标准相比，这代表了吞吐量的显著增加。因此，Nanolytics的EW平台具有独特的定位，可以帮助加速药物发现过程。Nanolytics将设计并商业化一种使用极小体积的仪器，以促进有效和安全治疗药物的开发。根据目前的数据，这种仪器的实施将代表生物制药公司最大的单一成本节约机会。

DESCRIPTION (provided by applicant): The objective of this proposal is to develop a fully integrated nanoliter droplet (nanodroplet)-based electrowetting (EW) device to accelerate the drug discovery process, in particular the field of adsorption, distribution, metabolism, excretion, and toxicology (ADMET). Traditionally, drug discovery has been a sequential process from therapeutic target identification/validation to primary screening for initial (lead) chemical compounds to chemical optimization for potency. These steps are followed by ADMET evaluation, pre-clinical/clinical trials, manufacturing and marketing. Recent data suggests 80% of all potential drugs are eliminated from the pipeline due to poor ADMET properties. This observation has caused a dramatic change in the process. The biopharmaceutical industry is now searching for technologies that will enable the simultaneous screening of chemical compounds for optimal therapeutic potency and the most favorable ADMET properties. By promoting only chemical leads that possess this combination of appropriate "drug- like" characteristics, it is predicted that the pharmaceutical development will realize a dramatic cost savings and accelerate the overall drug development process. In Phase I, we intend to demonstrate the applicability of EW to various ADMET methodologies. Several simple biochemical assays have already been demonstrated on our platform. However, for ADMET, more complex systems are often employed. Therefore, our studies will demonstrate the ability to perform microsomal cytochrome P-450 assays, adherent and non-adherent cell-based assays, and quantitative polymerase chain reaction. This family of protocols will serve an experimental foundation for the integration of a large suite of ADMET assays in Phase II. The biochemical versatility of the EW platform is attractive, as are several other features of EW. By utilizing only nanodroplets, each assay requires ~1,000 times less reagents compared to current methods. Thus, precious chemical compounds, target proteins, and cell lines used in the drug screening process are conserved. In addition, EW facilitates the rapid execution of multiple assay protocols concurrently. So, in Phase II, we anticipate a single chip generating greater than 100,000 data points/day. This represents a dramatic increase in through-put versus the industry screening standard. Consequently, the Nanolytics' EW platform is uniquely positioned to help facilitate the acceleration of the drug discovery process. Nanolytics will design and commercialize an instrument that uses extremely small volumes to facilitate the development of effective and safe therapeutic drugs. Based on current data, implementation of this kind of instrument would represent the single largest cost savings opportunity for biopharmaceutical companies.