19F-NMR-Based Dual-Site Reporter Assay for the Discovery and Distinction of Catalytic and Allosteric Kinase Inhibitors

摘要

src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/amclct/2017/amclct.2017.8.issue-6/acsmedchemlett.7b00084/20170606/images/medium/ml-2017-00084g_0004.gif">In modern kinase drug discovery, allosteric inhibitors have become a focus of attention due to their potential selectivity, but such compounds are difficult to identify. Here we describe an NMR-based competition assay using 19F-containing reporter molecules, which allows for rapid identification and discrimination between ATP-competitive and allosteric kinase inhibitors. We illustrate the principle of such a dual-site competition assay with the example of catalytic and allosteric ABL1 kinase inhibitors. The assay can also be used to identify and characterize mixed binding modes of well-known drugs, as shown for crizotinib and fingolimod.