Acquisition of inhibitor-sensitive protein kinases through protein design.
Protein phosphorylation is the major post-translational modification used by eukaryotic cells to control cellular signaling. Protein kinases have emerged as attractive drug targets because heightened protein kinase activity has been associated with several proliferative diseases, most notably cancer and restenosis. Until now, it has been very difficult to confirm the utility of protein kinases as inhibitor targets because very few small molecules that selectively inhibit one particular kinase are known. Discovery of highly specific kinase inhibitors has been slow because the protein family contains approximately 2000 members, all of which share a conserved active site fold. Recent work in several laboratories has sought to circumvent the problem of kinase structural degeneracy by engineering drug sensitivity into Src family tyrosine kinases and mitogen-activated protein kinases through site-directed mutagenesis. By introducing a unique non-naturally occurring amino acid into a conserved region of the enzyme's binding site, a target protein kinase can be rapidly sensitized to a small molecule. Introduction of the engineered kinase into a cell line or animal model should greatly expedite the investigation of protein kinase inhibition as a viable drug treatment. The purpose of this review is to summarize these recent advances in protein kinase drug sensitization.
Bishop
A C
AC
Department of Chemistry, Princeton University, NJ 08544, USA.
Shokat
K M
KM
D000818:Animals; D015195:Drug Design; D005347:Fibroblasts / Q000473:pathology; D005544:Forecasting; D006801:Humans; D066298:In Vitro Techniques; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics*; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011506:Proteins / Q000138:chemical synthesis*; D012680:Sensitivity and Specificity; D017385:Sequence Homology; D019061:src-Family Kinases / Q000235:genetics*
D047428:Protein Kinase Inhibitors; D011506:Proteins; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases