The cost of drug discovery and development is increasing, while the rate of new drug approvals is declining. In contrast to major technological advances with in silico and in vitro screening tools, there have been almost no advances in the tools available for establishing the actions of agents in the complex biochemical networks characteristic of fully assembled living systems. The resulting poor capacity to predict clinical response underlies the high attrition rate of leads at every step of drug development. A potential solution would be provided by kinetic biomarkers (in vivo measurement of fluxes though the key pathways that drive disease processes and therapeutic response). Novel approaches using stable isotope labeling with mass spectrometric analysis have recently emerged for measuring molecular kinetics relevant to drug targets with some applications to drug development. This review discusses the general principles of kinetic biomarkers, providing examples where kinetics have generated meaningful insights into drug activity and highlighting areas where the application of kinetic biomarkers may be particularly useful for future drug discovery and development. Stable isotope mass spectrometric technologies may provide a parallel efficiency for converting molecules into approved drugs with sufficient throughput and reproducibility to maintain pace with the modern engine for generating leads.

中文翻译：

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动力学生物标志物在临床前和临床药物开发中的新兴应用。

药物发现和开发的成本在增加，而新药的批准率正在下降。与计算机模拟和体外筛选工具的重大技术进步相比，用于在完全组装的生活系统特征的复杂生化网络中建立作用剂的工具几乎没有进展。在药物开发的每个步骤中，导致的较低的预测临床反应的能力不足导致铅的高损耗率。潜在的解决方案将由动力学生物标记物提供（通过驱动疾病过程和治疗反应的关键途径对通量进行体内测量）。最近出现了使用稳定同位素标记和质谱分析的新方法，用于测量与药物靶标相关的分子动力学，并将其应用于药物开发。这篇综述讨论了动力学生物标志物的一般原理，并提供了一些实例，其中动力学已经对药物活性产生了有意义的见解，并重点介绍了动力学生物标志物的应用可能对未来药物发现和开发特别有用的领域。稳定的同位素质谱技术可以提供并行的效率，以足够的通量和可重复性将分子转化为批准的药物，以保持与现代产生线索的引擎的步伐。提供了动力学已对药物活性产生有意义的见解的实例，并突出了动力学生物标记物的应用可能对未来药物发现和开发特别有用的领域。稳定的同位素质谱技术可以提供并行的效率，以足够的通量和可重复性将分子转化为批准的药物，以保持与现代产生线索的引擎的步伐。提供了动力学已对药物活性产生有意义的见解的实例，并突出了动力学生物标记物的应用可能对未来药物发现和开发特别有用的领域。稳定的同位素质谱技术可以提供并行的效率，以足够的通量和可重复性将分子转化为批准的药物，以保持与现代产生线索的引擎的步伐。