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.
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