Targeting inactive kinases: structure as a foundation for cancer drug discovery
2008
This chapter focuses on highlighting the structural plasticity of protein kinases and on the key role that structure guided techniques can impart to exploit this flexibility in the design of new drugs. Regardless of the distinct mechanisms that have evolved to maintain any one particular kinase in an inactive state, all active kinases share critical common structural features necessary to perform the phosphoryl transfer. By virtue of this fact, drug compounds that target active kinases often display significant off-target effects due to cross-inhibition of other kinases in the cell. While these multi-targeted inhibitors can be effective in the clinic, particularly for cancer chemotherapy, their inherent toxicity can limit both the timing and dosing of the drug. The success of STI-571 as a highly specific drug has demonstrated that targeting the unique inactive kinase structure that underlies the disease can attain spectacular clinical results. These results, coupled with recent developments for other inactive kinase inhibitor co-crystal structures, show promise for the successful structure based drug design and development of specific and targeted cancer therapies. Protein kinases are master regulatory switches that control the growth and proliferation of cells. In response to specific metabolic signals, protein kinases phosphorylate and activate target proteins that amplify the signal into cellular growth cascades.
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