Rational and precise targeting of oncogene-driven signalling is a crucial and yet today outstanding challenge in cancer research. Understanding the structural and molecular bases of oncogene activation and signalling is key for the design and development of better therapeutics. Our research focuses on the structural and molecular understanding of protein kinase function: how protein kinases are activated and regulated by post-translational modifications and allosteric inputs, and how they assemble into macromolecular protein complexes to transmit signals inside the cell. We put a special emphasis on how these mechanisms are corrupted in cancer due to oncogenic mutations and other oncogenic insults. Crucially, such atomic and molecular information can be translated into the design and development of next generation protein kinase inhibitors for targeted and personalised therapies.
We apply an integrated and multidisciplinary approach by combining: molecular biology for the generation of suitable constructs; protein biochemistry and biophysics for protein purification, quality assessment and functional evaluation; mass spectrometry (MS) for the identification and quantification of post-translational modifications; X-ray crystallography for the 3D-visualisation of proteins; and Drosophila as an in vivo model for data validation. Furthermore, we use structure-guided drug discovery and MD simulation approaches to exploit structural and functional vulnerabilities for drug design and development.