Phosphatidylinositol 3-kinases (PI3Ks) are vital regulators of intracellular signaling pathways and PI3K inhibitors are prominent targets in drug discovery, especially in cancer. PI3Ks catalyse the phosphorylation of phosphatidylinositol at the 3′-position of the inositol ring and the resulting secondary by-products are implicated in various cellular activities including cell survival, growth and proliferation. While class I PI3K has been intensively studied, the members of class II PI3K have gained attention recently and are believed to be up-regulated in certain types of cancers. The class II PI3Ks consists of three mammalian isoforms: PI3KC2α, PI3KC2β and PI3KC2γ but as yet there are no potent, selective inhibitors of class II PI3Ks.

We have generated a homology model of PI3KC2β and carried out molecular docking studies of known class I PI3K inhibitors that also show activity against PI3KC2β. Our docking results have revealed that while the overall binding poses are common for the two classes, there are non-conserved residues involved in interactions with these compounds that could be targeted for selectivity. To pursue a screening program based on these concepts, we have expressed and purified active PI3KC2β. Compounds from within our 400 compound PI3K inhibitor library are being screened as our first step to develop novel PI3KC2β-selective inhibitors.