Kinase Inhibitors: New and Improved!

Science's STKE  26 Sep 2000:
Vol. 2000, Issue 51, pp. tw6
DOI: 10.1126/stke.2000.51.tw6

Identifying the pathways in which kinases function leads to a greater understanding of what proteins are important for physiological processes. Inhibiting a specific protein kinase's activity often reveals whether that kinase is critical to a signaling pathway. However, the generation of supposed specific kinase inhibitors is tenuous at best. Shokat and colleagues have recently developed kinase mutants that accommodate bulky ATP analog kinase inhibitors yet retain near-wild-type kinase activity in the absence of the inhibitors. Wild-type protein kinases are unable to bind the bulky inhibitors. Bishop et al. now show that by engineering such mutations in Saccharomyces cerevisiae cdc28, a protein kinase intimately involved in cell-cycle control, ATP analogs can be used in vivo to inhibit mutant cdc28 activity and to affect cell division. Inhibitor treatment also reduced the levels of mRNA transcripts expressed at the G2/M cell-cycle boundary. Thus, a new generation of engineered kinases and inhibitors may provide greater flexibility and reliability to the study of kinase activity in vivo.

Bishop, A.C., Ubersax, A.J., Petsch, D.T., Matheos, D.P., Gray, N.S., Blethrow, J., Shimizu, E., Tsien, J.Z., Schultz, P.G., Rose, M.D., Wood, J.L., Morgan, D.O., Shokat, K.M. (2000) A chemical switch for inhibitor-sensitive alleles of any protein kinase. Nature 407: 395-401. [Online Journal]