Jones Lyn H
WorldWide Medicinal Chemistry, Pfizer, 610 Main Street, Cambridge, MA 02139, USA.
Future Med Chem. 2015;7(16):2131-41. doi: 10.4155/fmc.15.100. Epub 2015 Oct 29.
Chemical biology has a significant role to play in the discovery and validation of new therapeutic targets. Activity- and affinity-based probes have demonstrated considerable promise in the drug discovery setting as they provide a chemoproteomic means to confirm and quantify target engagement and selectivity of small molecule drug candidates. Many of these technologies have been developed using cell lysate (through the use of resin-immobilized enzyme inhibitors for example), but this does not represent the biology of an intact cell. This review highlights recent advances made in the design and application of cell-permeable probes that report on target activity and drug-target occupancy in living cells, thus providing a means to decipher molecular pharmacology and pathology in a more physiologically relevant manner.
化学生物学在新治疗靶点的发现和验证中发挥着重要作用。基于活性和亲和力的探针在药物发现领域已展现出巨大潜力，因为它们提供了一种化学蛋白质组学方法，用于确认和量化小分子候选药物的靶点结合及选择性。这些技术中的许多都是利用细胞裂解物开发的（例如通过使用树脂固定化酶抑制剂），但这并不能代表完整细胞的生物学特性。本综述重点介绍了在可穿透细胞的探针的设计和应用方面取得的最新进展，这些探针可报告活细胞中的靶点活性和药物 - 靶点占有率，从而提供一种以更生理相关的方式解读分子药理学和病理学的方法。
