Peptidomimetics as a new strategy to modulate Aurora-A and combat cancer

A new approach to targeting a protein involved in cell division, which can misfunction in cancer, has revealed new insights into how it functions. 

The protein, called Aurora-A, is one of a group of proteins called kinases. Kinases are enzymes which modify their targets to regulate many cell functions; they are commonly dysregulated in diseases such as cancer making them attractive targets for drug discovery. 

Aurora-A is of particular interest as a target for anti-cancer drugs because of its role in cell division. Although numerous clinical trials of drugs designed to inhibit Aurora-A have been undertaken, none have progressed into clinical use. This is because Aurora A has an essential role in all cells and so undesirable toxicity is common. 

To address this challenge, as part of the BBSRC-funded sLoLaprogramme – SPiDR – researchers in the University of Birmingham’s School of Chemistry have been looking to target protein-protein interactions involving Aurora A. Their results are published in Chemical Science. 

Aurora-A is an incomplete kinase, which means it relies on protein-protein interactions to regulate where it is in the cell and when it is switched on and off. By targeting these interactions, we might be able to more finely tune how we inhibit Aurora-A.”

Andrew Wilson, Professor, University of Birmingham

The team sought to inhibit the interaction of Aurora A with a protein called TACC3 using a peptidomimetic approach. They found that the most effective peptidomimetics were able to bind to Aurora-A and inhibit its interaction with TACC3 without inhibiting the enzymatic function of Aurora-A. 

Excitingly, the team also observed that the peptidomimetics were able to change the shape of Aurora-A in such a way as to inhibit a different protein-protein interaction at a remote site on Aurora-A. This second interaction between N-Myc and Aurora-A is particularly important. That’s because mis-regulation of Myc proteins is a hallmark of cancer and N-Myc plays a key role in childhood brain cancers. 

“Because Aurora-A stabilizes N-Myc against degradation, inhibiting the interaction could represent a promising approach for anticancer drug development and our finding that peptidomimetics can inhibit the N-Myc/Aurora-A interaction without inhibiting the enzyme function is therefore a significant observation,” explained Professor Wilson.