KMID : 0606920200280020172
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Biomolecules & Therapeutics 2020 Volume.28 No. 2 p.172 ~ p.183
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PBT-6, a Novel PI3KC2¥ã Inhibitor in Rheumatoid Arthritis
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Kim Ju-Young
Jung Kyung-Hee Yoo Jae-Ho Park Jung-Hee Yan Hong Hua Fang Zhenghuan Lim Joo-Han Kwon Seong-Ryul Kim Myung-Ku Park Hyun-Ju Hong Soon-Sun
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Abstract
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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¥ã in RA, and the underlying mechanism remains largely unknown. Therefore, we investigated the role of PI3KC2¥ã as a novel therapeutic target for RA and the effect of its selective inhibitor, PBT-6. In this study, we observed that PI3KC2¥ã was markedly increased in the synovial fluid and tissue as well as the PBMCs of patients with RA. PBT-6, a novel PI3KC2¥ã inhibitor, decreased the cell growth of TNF-mediated synovial fibroblasts and LPS-mediated macrophages. Furthermore, PBT-6 inhibited the PI3KC2¥ã 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¥ã is a therapeutic target for RA, and PBT-6 could be developed as a novel PI3KC2¥ã inhibitor to target inflammatory diseases including RA.
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KEYWORD
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Rheumatoid arthritis, Collagen-induced arthritis, PI3KC2¥ã, RANKL
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