Progress in the Development of Selective Inhibitors of Aurora Kinases

Abstract

Errors in the mitotic process are thought to be one of the principal sources of the genetic instability that hallmarks cancer. Unsurprisingly, many of the proteins that regulate mitosis are aberrantly expressed in tumour cells when compared to their normal counterparts. These may represent a good source of targets for the development of novel anti-cancer agents. The Aurora kinases represent one such family of mitotic regulators. In recent years there has been intense interest in both understanding the role of the Aurora kinases in cell cycle regulation and also in developing small molecule inhibitors as potential novel anti-cancer drugs. With several companies now starting to take Aurora kinase inhibitors into clinical development, the time is right to review the medicinal chemistry contribution to developing the field, in particular to review the increasingly broad range of small molecule inhibitors with activity against this kinase family.

The Suppression of Aurora-A/STK15/BTAK Expression Enhances Chemosensitivity to Docetaxel in Human Esophageal Squamous Cell Carcinoma

“…In the current study, we explored the possibility that the RNA interference -mediated suppression of Aurora-A could be used as a specific gene-targeting therapy to suppress the progression of ESCC. Moreover, the function of Aurora kinase inhibitors (including the patent literature) has been studied recently, revealing potentially promising anticancer (32,33). Therefore, our results in combination with these findings suggest that taxane-mediated chemotherapy could be more effective in combination with these anti-Aurora agents in ESCC.…”

RASSF1A interacts with and activates the mitotic kinase Aurora-A

“…Current thought is that overexpression induces centrosome defects, mitotic abnormalities and aneuploidy, which leads to cancer (Meraldi et al, 2004;Giet et al, 2005;Weaver and Cleveland, 2006). Being a putative oncogene, Aurora-A has attracted a great deal of attention as a potential antitumor target (Keen and Taylor, 2004;Mortlock et al, 2005;Naruganahalli et al, 2006). …”

Structural studies of B-type Aurora kinase inhibitors using computational methods

“…In earlier publications, a number of quinazoline-based series have been described as Aurora kinase inhibitors [2,22,[42][43][44] . Particularly, the p-benzamidoanilinoquinazoline series was shown to inhibit Aurora A and Aurora B equipotently.…”

“…Particularly, the p-benzamidoanilinoquinazoline series was shown to inhibit Aurora A and Aurora B equipotently. The investigation of the SAR around the anilino ring linking the key hinge (quinazoline) and the lipophilic pocket (benzamide) binding groups showed that this ring could be replaced with a number of heterocyclic systems to give improvements in both the potency and the physicochemical properties [42] . The linker group also has an important role for the cellular activity.…”

“…Compounds with elaborated C-7 side chains show good cellular activity and benefit from much better solubility and free drug levels. The quinazoline C-7 side chain might result in a further enhancement of the cellular potency [42] . In the thiazole series, the length of the aliphatic spacer, between the oxygen atom on the C-7 position of the quinazoline ring and the basic nitrogen atom within the side chain of the R1 substituent, governs the ability of the polar group to solvate [42] .…”