PBT-6, a Novel PI3KC2γ Inhibitor in Rheumatoid Arthritis

Phosphoinositide 3-kinase (PI3K) is considered as a promising therapeutic target for rheumatoid arthritis (RA) because of its involvement in inflammatory processes. However, limited studies have reported the involvement of PI3KC2 gamma in RA, and the underlying mechanism remains largely unknown. Therefore, we investigated the role of PI3KC2 gamma as a novel therapeutic target for RA and the effect of its selective inhibitor, PBT-6. In this study, we observed that PI3KC2 gamma was markedly increased in the synovial fluid and tissue as well as the PBMCs of patients with RA. PBT-6, a novel PI3KC2 gamma inhibitor, decreased the cell growth of TNF mediated synovial fibroblasts and LPS-mediated macrophages. Furthermore, PBT-6 inhibited the PI3KC2 gamma expression and PI3K/AKT signaling pathway in both synovial fibroblasts and macrophages. In addition, PBT-6 suppressed macrophage migration via CCL2 and osteoclastogenesis. In CIA mice, it significantly inhibited the progression and development of RA by decreasing arthritis scores and paw swelling. Three-dimensional micro-computed tomography confirmed that PBT-6 enhanced the joint structures in CIA mice. Taken together, our findings suggest that PI3KC2 gamma is a therapeutic target for RA, and PBT-6 could be developed as a novel PI3KC2 gamma inhibitor to target inflammatory diseases including RA.