Acquisition of inhibitor-sensitive protein kinases through protein design

Protein phosphorylation is the major post translational modification used b y eukaryotic cells to control cellular signaling. Protein kinases have emer ged as attractive drug targets because heightened protein kinase activity h as been associated with several proliferative diseases, most notably cancer and restenosis. Until now, it has been very difficult to confirm the utili ty of protein kinases as inhibitor targets because very few small molecules that selectively inhibit one particular kinase are known. Discovery of hig hly specific kinase inhibitors has been slow because the protein family con tains approximately 2000 members, all of which share a conserved active sit e fold. Recent work in several laboratories has sought to circumvent the pr oblem of kinase structural degeneracy by engineering drug sensitivity into Src family tyrosine kinases and mitogen activated protein kinases through s ite-directed mutagenesis. By introducing a unique non-naturally occurring a mino acid into a conserved region of the enzyme's binding site, a target pr otein kinase can be rapidly sensitized to a small molecule. Introduction of the engineered kinase into a cell line or animal model should greatly expe dite the investigation of protein kinase inhibition as a viable drug treatm ent. The purpose of this review is to summarize these recent advances in pr otein kinase drug sensitization. (C) 1999 Elsevier Science Inc. All rights reserved.