NOVEL ASSAY PLATFORM FOR ASESSING PROTEIN KINASE INHIBITORS

描述(申请人提供)：该SBIR项目的目标是开发一个用于筛选酪氨酸激酶抑制剂的新药发现平台。该平台的主要创新是使用了多酶分析，能够使用小体积样本实时测量效率并在单次实验中确定抑制机制。建议的平台解决了现有方法的缺陷，将试剂成本降低了十倍或更多；通过大幅减少分析时间和显著增加药物筛选过程的信息产量。该技术适用于高通量格式，并具有识别和研究变构激酶抑制剂的独特能力，这些抑制剂在治疗癌症、炎症性疾病、神经障碍和新陈代谢问题的新药开发中发挥着核心作用。与公共健康相关：蛋白激酶是最有前景的药物靶点之一，因为它在癌症、炎症性疾病、神经紊乱和新陈代谢问题等病理条件下发挥着至关重要的作用。目前，用于药物发现和开发的所有研究经费中约有25%用于新的激酶抑制剂，特别是发现具有更高的抑制效率、更低的毒性和更长的作用时间的变构抑制剂。然而，识别新的变构抑制剂是具有挑战性的，需要乏味的动力学和X射线衍射研究，这些研究成本高昂，劳动密集型，而且往往不能全面进行。该SBIR项目中正在开发的技术具有独特的识别和研究变构酶抑制剂的能力，能够以较低的成本快速提供更多信息。

DESCRIPTION (provided by applicant): The goal of this SBIR project is to develop a new drug discovery platform for screening tyrosine kinase inhibitors. The main innovation of the proposed platform is the use of a multi-enzyme assay, which is able to measure efficiency and identify inhibition mechanism in a single experiment in real-time using a small-volume sample. The proposed platform addresses the drawbacks of the existing methods by reducing the cost of reagents by ten times or more; by substantially reducing the assay time and significantly increasing the information yield of the drug screening process. The technology is adaptable to high through put format and has unique capabilities for identification and study allosteric kinase inhibitors, which play a central role in the development of new pharmaceuticals for treatment of cancer, inflammatory diseases, neural disorders, and metabolism problems. PUBLIC HEALTH RELEVANCE: Protein kinases represent one of the most promising groups of drug targets due to the vital role played by kinases in such pathological conditions as cancer, inflammatory diseases, neural disorders, and metabolism problems. Currently about 25% of all research spending on drug discovery and development is directed to new kinase inhibitors with a special focus on the discovery of allosteric inhibitors, which have a higher inhibition efficiency, lower toxicity and longer duration of action. Yet, identification of new allosteric inhibitors is challenging and requires tedious kinetic and X-ray diffraction studies, which are costly, labor intensive and too often are not carried out at the full extend. The technology under development in this SBIR project has a unique capability for identification and study allosteric kinase inhibitors and is able to provide more information quickly and at a lower cost.