Targeting PKC‐βII and PKB Connection: Design of Dual Inhibitors

Protein kinase C (PKC) has been the center of many cell signaling pathways. PKC isoforms, specifically PKC‐βII is linked to both diabetic complications as well as in promotion of angiogenesis and regulation of cancers. PKC‐βII activates the PKB/Akt pathway. Enzastaurin, a selective PKC‐βII inhibitor has been found to inhibit PKB/Akt by suppressing the regulation of various cancerous pathways. In the present work, we carried out an in depth study on the binding mode of inhibitors of PKC‐βII, enzastaurin and ruboxistaurin with the active site residues of PKB and PKC‐βII. A ligand based approach has been further used to determine the pharmacophoric features and spatial arrangement of molecules, having common properties necessary for appropriate binding to the active site of both targets. Virtual screening of the respective pharmacophores of both proteins led to identification of hits which may be useful for treatment of diabetic complications and cancer. The study has highlighted important features that may be considered in the future for designing novel inhibitors.