Screening of Protein Kinases by ATP-STD NMR Spectroscopy

摘要

Protein kinases are key mediators of cellular function:deregulation of kinase activity has been related to a wide range of diseases.Searching for potent inhibitors that are selective against the more then 500 potential human kinase targets is currently an active area of drug discovery.The identification of novel ATP-competitive kinase inhibitors is nonetheless challenging.Not only are corporate libraries deficient in compounds with kinase binding motifs,but also high throughput kinase assays are susceptible to a high rate of false positives.ATP typically binds to kinases with K_d's of 10-100muM;purine replacements would be expected to have similar affinities.This affinity range is difficult for many assay formats but ideal for NMR screening methods.While SAR-by-NMR is the best-known of these methods,ligand detected NMR screening methods (such as STD-NMR) are an excellent choice to screen for novel kinase cores.