Hit Identification for PKCzeta Inhibitors: Structure-Based Optimization, Virtual Screening, and Biological Evaluation

Protein kinase C zeta (PKCzeta) is believed to be a promising target for the treatment of some diseases, including inflammatory diseases, obesity and diabetes. Hit identification of PKCzeta inhibitors was conducted by structure-based modification, virtual screening and biological evaluation. Among all the compounds selected and synthesized, compound JW-1-60A showed moderate activity against PKCzeta at 30 microM and 100 microM. The molecular modeling studies showed that the binding mode of JW-1-61A was very close to the binding mode of JP-3-149, a reported PKCzeta inhibitor with very potent activity, which might partially explain the moderate activity of JW-1-61A. Based on the structure of JW-1-60A, we will synthesize a series of its analogs and investigate their selectivity against other kinases in the future.