Discovery of new PKN2 inhibitory chemotypes via QSAR-guided selection of docking-based pharmacophores

Serine/threonine-protein kinase N2 (PKN2) plays an important role in cell cycle progression, cell migration, cell adhesion and transcription activation signaling processes. In cancer, however, it plays important roles in tumor cell migration, invasion and apoptosis. PKN2 inhibitors have been shown to be promising in treating cancer. This prompted us to model this interesting target using our QSAR-guided selection of docking-based pharmacophores approach where numerous pharmacophores are extracted from docked ligand poses and allowed to compete within the context of QSAR. The optimal pharmacophore was sterically-refined, validated by receiver operating characteristic (ROC) curve analysis and used as virtual search query to screen the National Cancer Institute (NCI) database for new promising anti-PKN2 leads of novel chemotypes. Three low micromolar hits were identified with IC50 values ranging between 9.9 and 18.6 mu M. Pharmacological assays showed promising cytotoxic properties for active hits in MTT and wound healing assays against MCF-7 and PANC-1 cancer cells. [GRAPHICS]

Automated summary

Serine/threonine-protein kinase N2 (PKN2) plays important roles in cell cycle progression, migration, adhesion, and transcription activation signaling processes, as well as in cancer cell migration, invasion, and apoptosis. In this study, a QSAR-guided selection of docking-based pharmacophores approach was used to model PKN2 as a potential therapeutic target for cancer. Several pharmacophores were extracted from docked ligand poses and used to screen for new anti-PKN2 leads. Three promising compounds with low micromolar IC50 values were identified and showed cytotoxic properties against cancer cells in pharmacological assays.