Selective kinase inhibition by exploiting differential pathway sensitivity.
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.
Kung
Charles
C
Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, San Francisco, California 94143, USA.
Kenski
Denise M
DM
Krukenberg
Kristin
K
Madhani
Hiten D
HD
Shokat
Kevan M
KM
D001483:Base Sequence; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D004271:DNA, Fungal / Q000235:genetics; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D008954:Models, Biological; D000078183:Oxindoles; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
D004271:DNA, Fungal; D007211:Indoles; D000078183:Oxindoles; D047428:Protein Kinase Inhibitors; D029701:Saccharomyces cerevisiae Proteins; C022960:2-oxindole; D016203:CDC2 Protein Kinase; D018844:Cyclin-Dependent Kinases; C058605:PHO85 protein, S cerevisiae