The ability to inactivate multiple kinases is a desirable feature of a small-molecule inhibitor, as indicated by the widespread clinical efficacy of imatinib (Glivec). Is it possible to design drugs to have this characteristic? James Brown and colleagues have performed evolutionary analyses of Aurora-kinase sequences — particularly of ATP-binding domains — to uncover the best approach to target multiple members of this family.

The Aurora family of serine/threonine kinases regulate cell division and their expression levels are altered in various tumour types. Pharmaceutical companies have been developing small molecules that target the ATP-binding domain of these proteins, and these drugs can disrupt tumour-cell proliferation in vitro and in vivo. Mammals have Aurora-A, Aurora-B and Aurora-C, whereas frogs, fruitflies and nematodes carry only Aurora-A and -B. Fungi express a single Aurora homologue. Brown et al. analysed the sequences of all these various homologues to determine which protein domains are most closely related to the human genes, and might therefore be the best to study in animal models and in the design of inhibitors.

They found that although Aurora-A is ubiquitous among all vertebrates, Aurora-B and -C arose from a gene duplication in mammals. A comparison of the ATP-binding domains revealed that a stretch of 26 amino acids in the active site was identical between the human homologues of Aurora-B and -C, and varied by only 3 residues in Aurora-A. Inhibitors designed to target this region are likely to block the function of two or possibly all three of these enzymes, and might therefore be less susceptible to tumour resistance.