Development of triazole-based PKC-inhibitors to overcome resistance to EGFR inhibitors in EGFR-mutant lung cancers.

ABSTRACT

Protein kinase C delta (PKCδ) is prominently expressed in the nuclei of EGFR-mutant lung cancer cells, and its presence correlates with poor survival of the patients undergoing EGFR inhibitor treatment. The inhibition of PKCδ has emerged as a viable approach to overcoming resistance to EGFR inhibitors. However, clinical-grade PKCδ inhibitors are not available, highlighting the urgent needs for the development of effective drugs that target PKCδ. In this study, we designed and synthesized a series of inhibitors based on the chemical structure of a pan PKC inhibitor sotrastaurin. This was achieved by incorporating a triazole ring group into the original sotrastaurin configuration. Our findings revealed that the sotrastaurin derivative CMU-0101 exhibited an elevated affinity for binding to the ATP-binding site of PKCδ and effectively suppressed nuclear PKCδ in resistant cells in comparison to sotrastaurin. Furthermore, we demonstrated that CMU-0101 synergistically enhanced EGFR TKI gefitinib sensitivity in resistant cells. Altogether, our study provides a promising strategy for designing and synthesizing PKCδ inhibitors with improved efficacy, and suggests CMU-0101 as a potential lead compound to inhibit PKCδ and overcome TKI resistance in lung cancers.