Alternative assay formats to identify diverse inhibitors of protein kinases

作者：Singh Pirthipal^*; Ward Walter H J

来源：Expert Opinion on Drug Discovery, 2008, 3(7): 819-831.

DOI：10.1517/17530050802181056

• allosteric
• assay technology
• ATP-competitive
• binding
• high-throughput screening
• hit identification
• inhibitor
• kinase assay
• protein kinase

Background: Many protein kinases are targets for inhibition during drug discovery. Most first generation inhibitors bind at a site used by the purine moiety of ATP and were discovered in assays following inhibition of activated forms of protein kinases, often using model substrates. This approach presents challenges due to competition by ATP and ADP inside cells, achieving selectivity and securing intellectual property. Objective: To illustrate how increasingly diverse compounds are being identified in assays that target alternative forms of the protein kinase, such as forms with induced conformation changes or where binding occurs at other locations. Methods: We review how alternative formats for isolated protein assays may be based on binding rather than catalysis, or include non-activated kinase or physiological substrate. Conclusion: Future kinase assays will be designed to detect diverse inhibitors that use a wider, or different, range of binding sites.

• 出版日期2008-7