Kung Charles, Kenski Denise M, Krukenberg Kristin, Madhani Hiten D, Shokat Kevan M
Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, San Francisco, California 94143, USA.
Chem Biol. 2006 Apr;13(4):399-407. doi: 10.1016/j.chembiol.2006.02.004.
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.
蛋白激酶抑制剂经过优化，对其预期靶点具有高亲和力，以引发所需的细胞效应。在此，我们探讨了由细胞周期蛋白依赖性激酶Cdk1和Pho85控制的两条激酶信号通路之间的抑制敏感性差异是否足以实现对其中一条通路的选择性靶向。我们发现，尽管氧化吲哚抑制剂GW297361在体外对Cdk1的生化效力高20倍，但它在细胞中引发了Pho85选择性反应。我们提供的证据表明，对Pho85的部分抑制足以激活Pho85依赖性信号传导，但对Cdk1的部分抑制不足以阻断Cdk1依赖性细胞增殖。鉴定高敏感性激酶可能提供一种手段，以实现对激酶信号通路的选择性干扰，这与在体外IC50值之间实现最大差异的努力相辅相成。
