Understanding and Manipulating the Protein-Protein Interactions of Aurora A Kinase Using Chemical Biology Approaches

Aurora A is a kinase involved in mitosis during the cell cycle and has been found to
be overexpressed in many cancers, such as breast and ovarian. This makes Aurora
A an ideal target to develop anti-cancer treatments. Alisertib is an Aurora A
inhibitor that is currently in clinical trials, however it is not selective to Aurora A and
also inhibits Aurora B. This highlights the need to create selective Aurora A
inhibitors; this can be done by inspecting the protein-protein interaction Aurora A
is involved in. This project aims to develop protein-protein inhibitors for the TACC3-
Aurora A interaction by creating fragment-peptide hybrids using the dynamic
nature of hydrazone chemistry.
In this project, two TACC3 peptides, modified with hydrazone termini, were
designed and synthesised, alongside three control peptides and a tracer peptide.
The terminal hydrazone peptides were used in a fragment screen to identify
potential hybrids to compete at the TACC3/Aurora A site. From this screen a
peptide-fragment hybrid was identified and shown to have a >200-fold improved
competition compared to the parent peptide. The structure-activity relationship,
and structural basis of the activity of this hybrid was then explored. This was
achieved using X-ray crystallography and molecular docking, to confirm the
influence of the functional groups of the fragment on the affinity to Aurora A.
The concept of the fragment screen is an exciting prospect to explore further with
other Aurora A protein partners to discover potential selective Aurora A inhibitors.
This application of it with previous work by members of the group demonstrates its
cross compatibility across proteins. Future work with the identified hit hybrid could
develop it into a potential therapeutic to treat cancer.