Aurora kinase A is a mitotic kinase that plays a pivotal role in regulation of G2/M transition, centrosome maturation and separation, and bipolar spindle formation. The kinase is overexpressed in a wide range of solid tumours and cancer cell lines, where it is thought to contribute to genomic instability by causing erroneous chromosome segregation. Moreover, upregulation of Aurora A in vivo has been shown to override mitotic spindle checkpoint induced by Taxol and Cisplatin, suggesting that overexpression of the kinase can confer resistance to existing anticancer treatments.Rather than developing classical ATP-competitive inhibitors, which can suffer from selectivity and resistance issues, we aim to inhibit Aurora A by disrupting the interaction between the kinase and its regulatory protein TPX2. This key protein has been shown to activate, stabilise and correctly localise the kinase. In this report, we describe the progress made in developing a small-molecule protein-protein interaction inhibitor addressing common challenges, such as the shallow and featureless binding site.To date, we have established an assay cascade for identification and progression of inhibitors of the Aurora A � TPX2 interaction. Our high throughput screen of a tailored small-molecule library has yielded a number of hit compounds against the interaction and these are currently being validated by biophysical techniques such as NMR and ITC as well as novel phenotypic assays. We have used iterative rounds of synthetic chemistry and X-ray crystallography to determine structure activity relationships of the most promising hits. We envisage that this protein-protein interaction inhibition approach would lead to development of compounds selective against Aurora kinase A and that these could be used as tools for chemical biology as well as cancer therapeutics.

Development of small-molecule inhibitors of Aurora kinase A:TPX2 protein-protein interaction

248th National Meeting (2014)

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