Recent advances in PKC inhibitor development: Structural design strategies and therapeutic applications

Abstract

Protein kinase C (PKC) isozymes play critical roles in diverse cellular processes and are implicated in numerous diseases, including cancer, diabetes, and autoimmune disorders. Despite extensive research efforts spanning four decades, only one PKC inhibitor has received clinical approval, highlighting the challenges in developing selective and efficacious PKC-targeting therapeutics. Here we review recent advances in the development of small-molecule PKC inhibitors, focusing on structural design strategies, pharmacological activities, and structure-activity relationships. We analyze emerging approaches including fragment-based drug design, allosteric targeting, and natural product derivatization that have yielded promising new scaffold classes. Special attention is given to innovations in achieving isozyme selectivity, particularly for PKCα and PKCβ, which have proven crucial for therapeutic applications. We discuss how integration of computational methods, structural biology insights, and rational design principles has advanced our understanding of PKC inhibition mechanisms. This comprehensive analysis reveals key challenges in PKC drug development, including the need for enhanced selectivity and reduced off-target effects, while highlighting promising directions for future therapeutic development. Our findings provide a framework for designing next-generation PKC inhibitors with improved clinical potential.