Kinase Inhibitors

Kinase inhibitors: not just for kinases anymore. McGovern, S. L. & Shoichet, B. K. J. Med. Chem. (2003) Mar 12 (doi:10.1021/jm020427b)

Small-molecule kinase inhibitors are widely used as tools for understanding the physiological roles of particular kinases and as leads for drug design; however, their use is often complicated by their lack of specificity. Although this can partly be accounted for by the similarity of the ATP-binding site between kinases, some kinase inhibitors also inhibit enzymes not known to bind ATP. The authors show that for several widely used kinase inhibitors, their nonspecificity could be due to the formation of aggregates, and so results obtained from the use of these compounds should be interpreted cautiously.

Anticancer Drugs

Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Watkins, D. N. et al. Nature 422, 313–316 (2003)

Small-cell lung cancer (SCLC) is highly aggressive and has very limited treatment options. Watkins et al. show that activation of the Hedgehog pathway, which has a well-characterized role in development, is involved in some types of SCLC, and that blockade of this pathway could be a novel therapeutic strategy.

Anti-obesity Drugs

Crystal structure of the carboxyltransferase domain of acetyl-coenzyme A carboxylase. Zhang, H. et al. Science 299, 2064–2067 (2003)

Acetyl-coenzyme A carboxylases (ACCs), which regulate fatty acid biosynthesis, are a possible target for anti-obesity drugs. The carboxy-terminal (CT) domain of ACCs is also the target of several herbicides. Zhang et al. determined the structure of the CT domain of an ACC from yeast, and identified the probable area of the active site targeted by herbicides, thereby providing a starting point for the development of inhibitors of human ACCs.

Anticancer Drugs

A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. Cools, J. et al. N. Engl J. Med. 348, 1201–1214 (2003)

Hypereosinophilic syndrome (HES) is a fatal blood disease that is characterized by an increase in inflammatory white blood cells. Cools et al. evaluated imatinib (Gleevec/Glivec; Novartis) in eleven patients with HES, nine of which had positive responses, and found evidence that the activity of imatinib could be due to inhibition of a tyrosine kinase produced by the fusion of the PDGFRA and FIPL1 genes.