Selective kinase inhibition by exploiting differential pathway sensitivity.

Chemistry & Biology
Charles KungKevan M Shokat

Abstract

Protein kinase inhibitors are optimized to have high affinity for their intended target(s) to elicit the desired cellular effects. Here, we asked whether differences in inhibitory sensitivity between two kinase signaling pathways, controlled by the cyclin-dependent kinases Cdk1 and Pho85, can be sufficient to allow for selective targeting of one pathway over the other. We show the oxindole inhibitor GW297361 elicits a Pho85-selective response in cells despite having a 20-fold greater biochemical potency for Cdk1 in vitro. We provide evidence that partial inhibition of Pho85 is sufficient to activate Pho85-dependent signaling, but partial inhibition of Cdk1 is not sufficient to block Cdk1-dependent cell proliferation. Identification of highly sensitive kinases may provide a means to achieve selective perturbation of kinase signaling pathways complementary to efforts to achieve maximal differences between in vitro IC50 values.

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Citations

Jul 2, 2009·Journal of Chemical Biology·Lynette A Smyth, Ian Collins
Mar 16, 2007·Assay and Drug Development Technologies·Shan JiangJ Andrew Whitney
Nov 17, 2006·Nature Chemical Biology·Ian Collins, Paul Workman
Dec 10, 2015·Protein Science : a Publication of the Protein Society·Stephen N FloorJennifer A Doudna
Jan 30, 2009·Basic & Clinical Pharmacology & Toxicology·Rogelio Paniagua-PérezJavier Pérez-Gallaga
Jan 15, 2015·Science Signaling·Justin G EnglishHenrik G Dohlman
Mar 6, 2007·Nature Chemical Biology·Jimmy A BlairKevan M Shokat
Apr 28, 2007·Chemical Biology & Drug Design·Michael T NehilR Scott Lokey
Mar 3, 2007·The Journal of Organic Chemistry·Yoni EngelMichael Gozin

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