Skora Lukasz, Jahnke Wolfgang
Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland.
ACS Med Chem Lett. 2017 Apr 6;8(6):632-635. doi: 10.1021/acsmedchemlett.7b00084. eCollection 2017 Jun 8.
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 F-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.
在现代激酶药物研发中，变构抑制剂因其潜在的选择性而成为关注焦点，但此类化合物难以鉴定。在此，我们描述了一种基于核磁共振的竞争分析方法，该方法使用含氟报告分子，可快速鉴定和区分ATP竞争性激酶抑制剂与变构激酶抑制剂。我们以催化性和变构性ABL1激酶抑制剂为例，阐述了这种双位点竞争分析的原理。该分析方法还可用于鉴定和表征知名药物的混合结合模式，如克唑替尼和芬戈莫德所示。
