Non-ATP-competitive kinase inhibitors - enhancing selectivity through new inhibition strategies.

Background: ATP-competitive inhibitors of protein kinases have been successfully developed for life-threatening indications such as cancer. However, owing to the similarity of the ATP binding sites between kinases, it has been challenging to identify specific inhibitors. The progress towards the generation of kinase inhibiting drugs for more chronic indications has been slowed by the concern that low specificity kinase inhibitors will have undesired toxicities. Objective and methods: We have reviewed the scientific and patent literature to summarize alternative strategies that are being used to develop non-ATP-competitive kinase inhibitors with greater selectivity. Results/conclusion: Several new approaches are being taken to achieve selectivity. Among these, the use of small peptide therapeutics is particularly promising and is already yielding drugs that are demonstrating promise in human clinical trials.