High Throughput Screening Technology for Allosteric Kinase Inhibitors

描述(由申请人提供)：蛋白激酶在许多信号通路中发挥核心作用，是细胞功能的关键效应器。蛋白激酶活性的异常，要么是由于酶水平的变化，要么是由于激酶结构的突变，是导致病理的原因。因此，蛋白激酶抑制剂有可能被开发为许多疾病的治疗药物，包括癌症、中枢神经系统疾病和炎症。药物发现工作已经初步确定了与ATP结合直接竞争的小分子配体。然而，通过与高度保守的ATP结合来抑制一种酶的分子通常会抑制其他酶，从而导致潜在的药物安全问题。将药物靶向非活性构象的方法可能提供识别选择性抑制剂的手段。问题是，没有很多方法可以检测蛋白激酶的非活性构象，也没有一种方法可以轻松地用于药物发现。Encode Bio已经开发出一种光学技术，可以用来识别蛋白激酶的变构调节器，以稳定蛋白激酶的非活性构象。我们建议在开发药物发现方法方面取得下一次关键的技术飞跃，方法是建立一个系统，批量生产大型化学库高通量筛选所需的AsA试剂。与公共健康相关：蛋白激酶在调节大多数细胞功能方面发挥着重要作用。我们将开发具有普遍实用性的新型高通量检测方法，以确定结合在ATP结合位点之外的蛋白激酶抑制剂。这些检测可以用来加速许多疾病的治疗方法的开发，包括癌症、中枢神经系统疾病和炎症。我们将加快开发具有更好选择性和安全性的变构激酶抑制剂。

DESCRIPTION (provided by applicant): Protein kinases play a central role in many signaling pathways and are key effectors of cellular functions. Abnormalities in protein kinase activity, either due to changes in enzyme levels or mutations in the kinase structure, are responsible for pathologies. As such, protein kinases inhibitors can potentially be developed as therapeutics for many diseases, including cancer, central nervous system disorders and inflammation. Drug discovery efforts have primarily identified small molecule ligands that compete directly with ATP binding. However, molecules that inhibit one kinase by binding at the highly conserved ATP site often inhibit other kinases, resulting in potential drug safety issues. Approaches to target drugs to the inactive conformation may provide the means to identify selective inhibitors. The problem is that there are not many ways to detect the inactive conformation of protein kinases and none that can be easily employed for drug discovery. Encode Bio has developed an optical technology which can be employed to identify allosteric regulators of protein kinases that stabilize the inactive conformation of protein kinases. We propose to make the next critical technological jump in developing the approach for drug discovery by generating a system to mass produce the requisite assa reagents in quantities needed for high throughput screening of large chemical libraries. PUBLIC HEALTH RELEVANCE: Protein kinases play important roles in regulating most cellular functions. We will develop novel high throughput assays with universal utility to identify protein kinase inhibitors that bind outside the ATP-binding site. These assays could be used to accelerate the development of therapeutics for many diseases, including cancer, central nervous system disorders and inflammation. We will accelerate development of allosteric kinase inhibitors with potentially better selectivity and safety profiles.