Targeting PKC epsilon for the development of novel therapeutics for Type 2 diabetes

Lipid-activated protein kinase C epsilon (PKCε) plays an important role in insulin resistance and β-cell failure in Type2 Diabetes (T2D). Deletion or inhibition of PKCε improves β-cell function in genetic models of T2D and is therefore an excellent target for the development of novel therapeutics for T2D. Inhibitors of PKCε offer an alternative strategy for improving insulin availability in diabetic patients. The high degree of conservation of the catalytic site within the PKC family and among different kinases poses a serious hurdle for the development of PKCε isozyme specific inhibitors. An effective approach to selectively target PKCε activity is to prevent the interaction of PKCε with its adaptor protein, RACK2, which translocates PKCε from the cytosol to various sub-cellular sites. The N-terminal regulatory C2 domain of PKCε is critical for its interaction with RACK2, and peptides derived from the RACK-binding site of C2 domain have been shown to be selective inhibitors of RACK2/ PKCε interaction. Targeting this protein-protein interaction site with small molecules would facilitate the development of novel PKCε inhibitors with improved selectivity and pharmacokinetic properties. We have performed an NMR-based fragment screening to identify small molecules that bind to the C2 domain of PKCε. Several hits were identified in the primary screen, indicating that this protein-protein interaction site is druggable.

This project will validate the hits identified from the primary screen using various biophysical techniques (like SPR, ITC and NMR) and further elaborate the fragment hits into high-affinity ligands using medicinal chemistry optimisation.