Maisonneuve Team Structural Biology of (Pseudo)Kinases and Eukaryotic Signaling

Pseudokinases are inactive kinases that influence cell signaling through non-catalytic mechanisms. Pseudokinases represent ~10% of all human protein kinases. Their dysregulation contributes to human diseases, including cancers. They represent a promising niche of therapeutic targets. Indeed, the first drug targeting a pseudokinase protein, i.e. Deucravacitinib, was approved by the FDA in 2022, paving the way for the development of new therapeutics targeting pseudokinases. However, pseudokinases remain challenging targets due to their lack of catalytic activity and our lack of understanding of how they function. Therefore, uncovering the molecular mechanisms of pseudokinases would not only improve our understanding of human signaling in health and disease, but would also allow us to better target them in the clinic.

To shed light on how pseudokinase proteins work, our group combines integrative structural biology approaches (cryo-EM, X-Ray crystallography and NMR), biophysics characterization, functional assays (in vitro and in cell) and development of pseudokinase-targeting small molecules. Such molecules are exploited as chemical tools to decipher the molecular mechanism of pseudokinase proteins but also to address key questions about their biological function. These molecules may also represent proof-of-concept pre-clinical chemical tools and set the stage for translational research to develop therapeutic lead compounds against various diseases.

(Figure reproduced from Boudeau et al., Emerging roles of pseudokinases, Trends in Cell Biology  (2006) 10.1016/j.tcb.2006.07.003)