Chemical genetic analysis of signal transduction pathways

Abstract

Covalent modification of proteins by phosphorylation represents a major mechanism of signal transduction that contributes to many physiological and pathophysiological processes. The enzymes that regulate protein phosphorylation (e.g., protein kinases and phosphatases) are, therefore, potential targets for the rational design of small-molecule drugs for the treatment of many diseases. A critical aspect of drug design is the reliability of proof-of-principle studies that demonstrate the therapeutic potential of the drug target. Studies using genetically modified mouse models that lack expression of the drug target using gene ablation and RNAi-based technologies have been widely employed. Recently, an alternative strategy using a chemical genetic approach has been proposed. Here, the authors discuss the strengths and weaknesses of the chemical genetic approach for studies of target validation.

Keywords::

• chemical genetics
• protein kinase
• signal transduction

Acknowledgements

The authors thank Kevan Shokat for helpful discussions on the chemical genetic strategy. This work was supported by a grant from the National Cancer Institute.