Translating Isolated Enzyme Inhibition to Efficacy Against the Native Kinase

3 Translating Isolated Enzyme Inhibition to Efficacy Against the Native Kinase 

As well as its effect on the translation of inhibitory potency against the intended target to cellular activity, the complex whole-cell situation can have a profound effect on the observed selectivity of kinase inhibitors. A small selection of data for the type II inhibitor sorafenib 8 demonstrates the potential for selectivity profiles to be different when comparing isolated enzyme or whole cell data, showing it to be a more potent inhibitor of Flt-3 relative to VEGFR-2, PDGFR-p and c-Kit in cells than would be predicted from its kinase inhibitory profile (Table 3.2).23 Probing the mechanistic basis for cellular kinase inhibitor selectivity, researchers at the University of California demonstrated that differential pathway sensitivity could lead to selective effects in cells.24 

CDK2 IC50 2 nM CDK2 IC50 9 nM Met IC501 nM Met IC50 4 nM 

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