PI5P4K Subtype-selective Inhibitors: Three Binding Modes from One Privileged Motif
Henriëtte Willems, Greg Aldred, Steve Andrews, Helen Boffey, Stephen Chawner, Jon Clarke, Simon Edwards, Christopher Green, Tamara Romero, Tim Rooney, Duncan Scott, John Skidmore and David Winpenny
ALBORADA Drug Discovery Institute, University of Cambridge, UK
The phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) play a central role in regulating cell signalling pathways and, as such, have become therapeutic targets for diseases such as cancer, neurodegeneration and immunological disorders. The PI5P4Ks are lipid kinases, for which three highly homologous isoforms are known: α, β and γ. They have very low homology to eukaryotic protein kinases, and no structural similarity in the active site.
We have developed PI5P4Kα and PI5P4Kγ inhibitors that are both subtype-selective and selective against a wide panel of kinases.[1,2] Two series of inhibitors were developed from virtual screening hits and a third series from literature compound NIH-12848. All three series share the privileged aminopyrimidine kinase motif, but crystallography has shown that the three series have distinct binding modes. A novel allosteric binding mode was discovered for one series of inhibitors. Furthermore, the crystal structures show that water molecules play an important role in selectivity that is difficult to predict from the apo structure.
Ab initio calculations and a comparison of the conformations of the bound ligands with small molecule crystal structures suggest that small substituent changes can have a large conformational effect in these PI5P4K inhibitors, that can be exploited to modulate potency and selectivity.