Editors' ChoiceDRUG DESIGN

The Devil Is in the Details

Science's STKE  31 May 2005:
Vol. 2005, Issue 286, pp. tw209
DOI: 10.1126/stke.2862005tw209

Protein phosphorylation is a major regulatory mechanism for control of many aspects of cellular function and is catalyzed by enzymes known as protein kinases. Modulation of the activity of protein kinases thus offers many opportunities for the development of therapeutically beneficial drugs. However, the catalytic domains of the protein kinases are very similar, so it has been a challenge to identify or design specific inhibitors. Cohen et al. (see the Perspective by Ahn and Resing) overcame this problem through careful analysis of the kinase catalytic sites and comparison of the known sequences of the nearly 500 human protein kinases. They combined two distinctive properties of the catalytic site of the RSK1 and RSK2 protein kinases in order to design small-molecule inhibitors that potently and selectively blocked activity of the RSK enzymes in vitro and in vivo.

M. S. Cohen, C. Zhang, K. M. Shokat, J. Taunton, Structural bioinformatics-based design of selective, irreversible kinase inhibitors. Science 308, 1318-1321 (2005). [Abstract] [Full Text]

N. G. Ahn, K. A. Resing, Lessons in rational drug design for protein kinases. Science 308, 1266-1267 (2005). [Summary] [Full Text]