Designer Peptides for Key Protein-Protein Interactions of Aurora A Kinase

Aurora A is a Ser/Thr protein kinase that has canonical roles in mitotic entry and bipolar spindle assembly. The kinase is frequently dysregulated in cancers and has been pursued for decades as a promising anti-cancer target. Although a number of highly potent and selective ATP competitive Aurora A inhibitors have been developed and entered clinical trials, none have progressed to clinical use. Aurora A localization and activation is reliant on the formation of protein-protein interactions (PPIs) with multiple binding partners. For example, Aurora A PPIs with the microtubule-associated proteins TPX2 and TACC3 are crucial for the stabilization of microtubules during bipolar spindle assembly. Aurora A also interacts with the transcription factor N-Myc, another established anti-cancer target. Using recently determined crystal structures for Aurora A in complex with N-Myc, TPX2 and TACC3, the main aim of this work was to design and develop selective, peptidomimetic inhibitors for these key Aurora A PPIs; such inhibitors could act as powerful tools for further study and starting points for the development of novel chemotherapeutics based on PPI inhibition.